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Aspirin and nonsteroidal anti-inflammatory drugs have been related to decreased risk of several cancers, but studies on the relation with the risk of renal cell cancer (RCC) are inconsistent. A case–control study of RCC was conducted in Italy between 1992 and 2004. Cases were 755 patients with incident, histologically confirmed RCC, and controls were 1297 patients in hospital for acute non-neoplastic conditions. Odds ratios (OR) and 95% confidence intervals (CI) for RCC were conditioned on center, sex, age, and year of interview, and adjusted for education, smoking, alcohol consumption, diabetes, and hypertension. Regular use of aspirin for at least 6 months was reported by 67 cases and 99 controls, corresponding to an OR of 0.98 (95% CI 0.69–1.38). The ORs were 0.91 (95% CI 0.55–1.50) in regular users for less than 3 years, and 1.04 (95% CI 0.67–1.63) in users for 3 years or longer; 0.47 (95% CI 0.20–1.12) when aspirin was used as analgesic and 1.10 (95% CI 0.75–1.62) when it was used for cardiovascular disease prevention. No significant heterogeneity was found for regular use of aspirin across strata of age and sex. This study, based on a large dataset, suggests that regular use of aspirin did not increase RCC risk.