The relation between lifelong physical activity at work and during leisure-time and the risk of renal cell cancer (RCC) was analyzed in a case-control study conducted in Italy between 1992 and 2004. Cases were 767 subjects with incident, histologically confirmed RCC, and controls were 1,534 patients hospitalized for acute nonneoplastic conditions. Odds ratios (OR) and 95% confidence intervals (CI) for RCC were computed by multiple logistic regression models, conditioned on study center, sex and age, and adjusted for main covariates. Compared to the lowest level of occupational physical activity, the multivariate OR of RCC for the highest level were 0.65 (95% CI 0.49–0.87) at age 12 years, 0.67 (95% CI 0.53–0.84) at age 15–19, 0.74 (95% CI 0.59–0.93) at age 30–39 and 0.71 (95% CI 0.55–0.92) at age 50–59 years, with significant inverse trends in risk. The inverse association was consistent in strata of sex, age at diagnosis, body mass index, smoking habit and alcohol drinking. No significant association was found for leisure-time physical activity. The inverse association between occupational physical activity and RCC risk, if real, may be related to the effects of insulin-like growth factors, or lipid peroxidation and about 9% of cases of RCC in Italy could be avoided by increasing physical activity. However the inverse association might involve confounding by indirect mechanisms, such as body composition or other social class correlates. © 2006 Wiley-Liss, Inc.