The role of selected macronutrients, fatty acids and cholesterol in the etiology of renal cell carcinoma (RCC) was analyzed using data from a case–control study conducted in 4 Italian areas between 1992 and 2004. Cases were 767 patients with incident, histologically confirmed RCC, admitted to major teaching and general hospitals of the study areas. Controls were 1,534 subjects admitted for acute, nonneoplastic conditions to the same hospitals. Information on dietary habits and nutrient intake was elicited using a validated food frequency questionnaire including 78 food groups and recipes. Odds ratios (OR) and 95% confidence intervals (CI) for increasing levels of nutrient intake were estimated after allowance for total energy intake and other potential confounding factors. A direct association with RCC was found for starch intake (OR = 1.9 for highest versus lowest quintile of intake; 95% CI: 1.4–2.6, p-value for trend = 0.001), while an inverse association was found for fats from vegetable sources (OR = 0.6; 95% CI: 0.5–0.8; p-value for trend = 0.002), unsaturated fatty acids (OR = 0.5; 95% CI: 0.4–0.7; p-value for trend = 0.0002), and polyunsaturated fatty acids (OR = 0.5; 95% CI: 0.4–0.7; p-value for trend = 0.001). Among polyunsaturated fatty acids, linoleic acid (OR = 0.5; 95% CI: 0.4–0.7; p-value for trend = 0.0001) and linolenic acid (OR = 0.7; 95% CI: 0.5–1.0; p-value for trend = 0.01) were inversely related to RCC. When 6 major macronutrients were included in the same model, the adverse effect of high intake of starch remained statistically significant, together with the protective effect of polyunsaturated fatty acids. Results were consistent in strata of age, body mass index, treated hypertension, energy intake, stage and family history of RCC. © 2008 Wiley-Liss, Inc.