The clinical course of renal cell carcinoma (RCC) is highly variable. Overexpression of the p53 protein has been suggested as a possible prognostic parameter in RCC. Overexpression of the mdm-2 oncogene product has been shown to interact with the p53 function. To investigate the immunohistochemical overexpression of mdm-2 protein in comparison with that of p53 protein in RCC, 50 nonpapillary pT3 RCCs were immunostained for p53 protein (DO-7) and mdm-2 (IF2). Tumor growth fraction (Ki-67 labeling index; MIB-1) was determined by immunohistochemistry. p53 positivity was detected in 16% of tumors. mdm-2 overexpression was seen in 30% of RCCs. There was a significant association between p53 and mdm-2 immunostaining (P = 0.0006), suggesting that mdm-2 protein may contribute to p53 protein stabilization in RCC. p53 overexpression was associated with a high Ki-67 LI (P = 0.0002), suggesting that p53 overexpression is involved in growth control in RCC. Survival analysis showed that Ki-67 LI (P = 0.04) and p53 overexpression were associated with poor prognosis (P = 0.0021), whereas mdm-2 overexpression was not related to patient outcome (P = 0.73). A Cox regression analysis revealed tumor stage (P < 0.001) and p53 overexpression (P < 0.05) to be independent prognostic parameters. It is concluded that p53 but not mdm-2 may be of practical relevance in predicting patient prognosis in RCC.