Limited data exist regarding whether a history of urinary tract infection (UTI) increases risk of developing renal cell carcinoma (RCC). Furthermore, it is unclear whether any association of RCC with a history of UTIs is modified by known risk factors for RCC (i.e., smoking, obesity). The authors report data from a 1986-1989 population-based case-control study in Iowa. RCC cases (233 males, 139 females) were identified through the Iowa Cancer Registry; controls (1,497 males, 751 females) were randomly selected from the general population, frequency matched on age and sex. Subjects provided detailed information on demographic, anthropometric, lifestyle, dietary, and medical history risk factors. In age-adjusted analysis, risk increased for subjects who self-reported a history of physician-diagnosed kidney or bladder infection (odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.5, 2.5) compared with those reporting no such history. Both sex and smoking status modified the risk of RCC associated with a history of UTI, with the strongest risk reported for males (OR = 2.7, 95% CI: 1.9, 3.8) and current smokers (OR = 4.3, 95% CI: 2.7, 6.7). The strongest risk was reported for male current smokers with a history of UTI (OR = 9.7, 95% CI: 5.0, 18.1). Multivariate adjustment for anthropometric, lifestyle, and dietary factors did not alter these findings. Results suggest a positive association of UTI history with RCC development, with elevated risks most notable for males with a history of smoking.