OBJECTIVE: To assess the associations of smoking, body weight, and physical activity with risk of undergoing total joint replacement (TJR) in a population-based cohort of men. METHODS: A cohort study of 11,388 men that integrated clinical data with hospital morbidity data and mortality records was undertaken. The risk of undergoing TJR was modeled on baseline weight, height, comorbidity, socioeconomic status, years of smoking, and exercise in 3 separate age groups, using Cox proportional hazards regressions and competing risk regressions (CRRs). RESULTS: Dose-response relationships between weight and risk of TJR and between smoking and risk of TJR were observed. Being overweight independently increased the risk of TJR, while smoking lowered the risk. The decreased risk among smokers was demonstrated in both Cox and CRR models and became apparent after 23 years of exposure. Men who were in the highest quartile (≥48 years of smoking) were 42-51% less likely to undergo TJR than men who had never smoked. Tests for trend in the log hazard ratios (HRs) across both smoking and weight quantiles yielded significant P values. Vigorous exercise increased the hazard of TJR; however, the association reached statistical significance only in the 70-74-year-old age group (adjusted HR 1.64 [95% confidence interval 1.19-2.24]). Adjusting for Deyo-Charlson Index or Elixhauser's comorbidity measures did not eliminate these associations. CONCLUSION: Our findings indicate that being overweight and reporting vigorous physical activity increase the risk of TJR. This study is the first to demonstrate a strong inverse dose-response relationship between duration of smoking and risk of TJR. More research is needed to better understand the role of smoking in the pathogenesis of osteoarthritis.