Previous studies of omega-3 fatty acids report improved outcomes where inflammation is a key factor. The objective of this systematic review is to evaluate effects of omega-3s on inflammatory biomarkers.Randomized clinical studies that measured the influence of omega-3 fatty acids on inflammatory biomarkers were identified using a comprehensive search. Eligible studies were rated with the American Dietetic Association Evidence Analysis Manual and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) process to examine study quality and risk/benefit.112 studies were included. Over 65% reported statistically significant effects. The majority were scored as low risk of bias (high quality) and scored strong (cardiac populations and critically ill) to weak (Alzheimer's Disease, hypertriglyceridemia/diabetes, and obesity) on the risk/benefit ratio evidence for modulation of inflammatory biomarkers. There was inadequate data to determine a GRADE for inflammatory biomarker studies for some conditions (healthy individuals, rheumatoid arthritis, metabolic syndrome, renal disease, pregnancy, or children).Clinical literature on the effects of omega-3 fatty acids on inflammatory biomarkers contains mostly small sample sizes, is neutral to high quality, and report mixed effects. Larger studies examining dose and delivery are needed.