ObjectivesWork schedule demands contribute to circadian disruption and may influence health via an inflammatory response. We examined the impact of shiftwork and long work hours on inflammation in a national US sample.MethodsParticipants included 12 487 employed black and white men and women aged ≥45 years enrolled in the REasons for Geographic and Racial Differences in Stroke Study who completed an occupational questionnaire (2011–2013) and clinical examination (2013–2016). Cross-sectional associations between shiftwork and work hours with log-transformed high-sensitivity C reactive protein (CRP) and white blood cell (WBC) count were examined by multiple linear regression analysis, overall and by race–sex subgroups.ResultsOverall, rotating shift workers had higher log-CRP concentration compared with day workers (β=0.09, 95% CI:0.02 to 0.16) and findings for WBC were null. Black women had the highest geometric mean CRP (2.82 mg/L), while white men had the highest WBC (6.35×109/L). White men who worked afternoons had higher log-CRP compared with those who worked days (β=0.20, 95% CI: 0.08 to 0.33). Black men engaged in shiftwork <10 years working ≥55 hours/week had higher log-CRP and log-WBC compared with those working days <55 hours/week (β=0.33, 95% CI: 0.02 to 0.64 and β=0.10, 95% CI: 0.003 to 0.19). Among shift workers, non-retired white women working forward and backward shift rotations had higher log-CRP compared with those working forward only (β=0.49, 95% CI: 0.02 to 0.96).ConclusionsShift workers had higher inflammatory markers compared with day workers and race–sex disparities should be examined further. These findings highlight a potential biological pathway linking work schedule demands and chronic disease.