The association of body size, lifestyle, and medical conditions with renal cell cancer risk was examined among 161,126 Hawaii-Los Angeles Multiethnic Cohort participants (1993-2002). After 8.3 years of follow-up, 347 renal cell cancer cases (220 men, 127 women) were identified. Renal cell cancer risk increased with increasing body mass index in men (multivariate relative risk (RR) = 1.06 per unit of body mass index, p = 0.001) and women (RR = 1.07, p < 0.0001). The relative risks associated with being obese compared with being lean were 1.76 (95% confidence interval (CI): 1.20, 2.58) for men and 2.27 (95% CI: 1.37, 3.74) for women. Hypertension was associated with renal cell cancer (RR-men = 1.42, 95% CI: 1.07, 1.87; RR-women = 1.58, 95% CI: 1.09, 2.28). Smoking was confirmed to be a risk factor for both sexes. Among women, diuretic use was associated with increased risk (RR = 1.63, 95% CI: 1.04, 2.57), whereas physical activity was associated with reduced risk (ptrend = 0.027). Alcohol consumption was inversely associated with risk for men (ptrend = 0.045). Compared with nondrinkers, men who drank >or=1 drinks/day had a 31% lower risk (95% CI: 0.49, 0.96). Results show that body mass index, smoking, and hypertension are risk factors for renal cell cancer in both sexes.