We conducted a case-control analysis, a family-based population analysis, and a meta-analysis to assess the role of family history of cancer and kidney cancer in association with the risk of renal cell carcinoma (RCC). A total of 325 cases and 329 controls were identified from an ongoing case-control study of RCC. Study variables were assessed through 45-minute structured face-to-face interviews. In the case-control analysis, a family history of any cancer (in first-degree relatives) was associated with a nonsignificant 1.2-fold increase in RCC risk [95% confidence interval (95% CI), 0.8-1.6]. The risk increased to 1.7 and became significant when the relative was a sibling (95% CI, 1.1-2.5). A family history of kidney cancer (kidney cancer in first-degree relatives) was associated with a 4.3-fold significantly increased risk of RCC (95% CI, 1.6-11.9). The cases reported a total of 2,536 first-degree relatives of which 21 (0.8%) had kidney cancer, and the controls reported a total of 2,333 first-degree relatives of which 5 (0.2%) had kidney cancer (P=0.003). In the family-based population analysis, a family history of kidney cancer was associated with a 2.8-fold increased risk of RCC (95% CI, 1.0-7.8). The meta-analysis further confirmed this significant association with a 2.2-fold increased risk of RCC (95% CI, 1.6-2.9). To our knowledge, this is the first study to use three analytic strategies to investigate the association between a family history of kidney cancer and risk of RCC, and the first systematic evaluation of the relative risk for developing RCC associated with family history.