Quadriceps weakness is a hallmark impairment of knee osteoarthritis (OA). Reduced quadriceps strength is one of the earliest clinical findings amon persons with knee OA emerging prior to patient-reported symptoms and observed disability and may play an integral role in disease development (31,32). Strength deficits in the OA population range from 15 to 18% in persons prior to disease development (31,32), to 24% in persons with Kellgren/Lawrence (K/L) grade II OA (18), to as high as 38% in persons with K/L grade IV knee OA (27). Collectively, these data highlight the pervasiveness of quadriceps impairments in knee OA and suggest that quadriceps weakness may be an identifiable risk factor for the development of knee OA and/or indicative of disease progression. Furthermore, quadriceps strength is an important determinant of functional performance (23,26). The presence of impairments in joint pain, instability, and stiffness as well as reduced physical activity and high incidences of functional disability are not surprising with the magnitude of strength deficits exhibited by individuals OA (23). Failing to address strength deficits may hold serious implications such as further joint deterioration and continued functional decline (24,29). Without appropriate intervention, the noted deficits associated with OA may persist following surgical intervention and limit functional recovery. To this end, a better understanding of the physiological basis of OA-related weakness is necessary to improve both early and preoperative management in persons with knee OA. Age-related changes in muscle are characterized by decreased lean muscle mass, fiber size, and fiber number along with increased intramuscular fat and connective tissue contributing to reduced force-generating capacity in older adults (7,20). While lean muscle mass is directly related to muscle strength in persons without knee pathology (3,11–14,25,41), the rate of decline in muscle strength exceeds the rate of decline in lean muscle mass. Muscle strength in healthy adults decreases by approximately 1.5–2.5% per year, beginning around the fifth decade of life (10,16), whereas lean muscle mass only decreases at a rate of only 1% per year, beginning around the sixth decade (16,19,21), highlighting that muscle atrophy alone is not implicitly responsible for the magnitude of age-related strength declines. Neuromuscular changes (e.g., reduced voluntary muscle activation and decreased contractile rate) help to explain the age-related discrepancy between the rates of strength decline and changes in muscle size (36,38). Unlike the relationship between strength and lean muscle mass, a linear model underestimates the presence of activation deficits (35). Use of a curvilinear model to estimate voluntary muscle activation demonstrates that muscle activation in healthy older adults (mean = 0.868 ± 0.018) is 11% lower than young adults (mean = 0.978 ± 0.005), helping to explain the discrepancy of strength loss with aging (38). Chronic disease such as OA seems to accelerate age-related changes in muscle properties (13,15,26). Muscle activation impairments are magnified in persons with knee OA ranging from 8 to 25% in populations of varying disease severity (4,13,18,37). Lower-extremity lean muscle mass is also smaller in persons with OA; however, the magnitude of this impairment and its role in explaining OA-related weakness is unclear (8,32,39). Gur and Cakin (8) found a moderate relationship between quadriceps cross-sectional area (CSA) and isokinetic strength in persons with bilateral K/L grade II–MI knee OA changes. This relationship between strength and CSA may be skewed because the computed topography measurements did not account for intramuscular fat. Furthermore, the study participants had bilateral involvement, so the degree of muscle atrophy could not be quantified without a control limb; comparison of the CSA values of Gur et al. with previously reported values in healthy persons suggests that muscle atrophy may not present in persons with OA (39), contradicting reports of decreased muscle mass in OA (32). Without data highlighting the degree of OA-related changes in muscle properties, the relative contributions of muscle atrophy and reduced voluntary muscle activation to explain quadriceps weakness in knee OA remain unknown. A better understanding of the mechanistic properties of quadriceps weakness in knee OA and the potential interactions between muscle atrophy, activation impairment, and strength will aid the development of appropriate and effective treatment interventions for persons with OA. The purpose of the current study was twofold: to quantify impairments in muscle composition and muscle activation in persons with K/L grade IV knee OA, and to determine the contributions of these impairments to explain quadriceps strength deficits. We hypothesized that compared with the contralateral, nondiseased limb, the OA limb would exhibit greater quadriceps weakness, greater muscle atrophy, and larger deficits in muscle activation. Secondly, we hypothesized that muscle activation deficits would have a larger impact on muscle strength in the OA limb than would lean muscle CSA.