Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the pathogenesis of osteoarthritis (OA). However, the link between these compounds and OA remains unknown. In this study, the authors investigated the association of OA with PFOA and PFOS in a population of 49,432 adults from 6 PFOA-contaminated water districts in the mid-Ohio Valley (2005-2006). Participants completed a comprehensive health survey; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history, including physician diagnosis of osteoarthritis, was assessed via self-report. Analyses included adjustment for demographic and lifestyle characteristics, body mass index, and other potential confounders. Reported OA showed a significant positive association with PFOA serum levels (for highest quartile of PFOA vs. lowest, adjusted odds ratio = 1.3, 95% confidence interval: 1.2, 1.5; P-trend = 0.00001) and a significant inverse association with PFOS (for highest quartile vs. lowest, adjusted odds ratio = 0.8, 95% confidence interval: 0.7, 0.9; P-trend = 0.00005). The relation between PFOA and OA was significantly stronger in younger and nonobese adults. Although the cross-sectional nature of this large, population-based study limits causal inference, the observed strong, divergent associations of reported OA with PFOA and PFOS may have important public health and etiologic implications and warrant further investigation.