Expression levels of p27kip1, a negative regulator of the G1 phase of the cell cycle, and 8‐hydroxydeoxyguanosine (8‐OHdG), a marker of oxidative DNA damage, were assessed by immunostaining in a series of renal cell carcinomas (RCCs) and their prognostic significance was evaluated. Expression of p27kip1 as well as of the α‐subunit of the dystroglycan (DG) complex, previously reported to be altered in RCC, was also evaluated by western blot analysis. Nuclear expression of p27kip1 was reduced in a significant fraction of tumors and low p27kip1 staining correlated with higher tumor grade (P < 0.01). Recurrence and death from clear cell RCCs were significantly more frequent in p27kip1‐low expressing tumors and Kaplan–Meier curves showed a significant separation between high vs low expressor groups for both disease‐free (P = 0.011) and overall (P = 0.002) survival. Low nuclear expression of p27kip1 as well as loss of α‐DG were confirmed to be independent prognostic parameters at a multivariate analysis and the simultaneous loss of both molecules defined a “high‐risk” group of patients with increased risk of recurrence (RR = 28.7; P = 0.01) and death (RR = 12.9; P = 0.03). No significant correlation with clinical or pathological parameters was found for 8‐OHdG staining. Western blot analyses suggested a post‐translational mechanism for the loss of α‐DG expression and demonstrated that cytoplasmic dislocation of the protein contributes to the loss of active nuclear p27kip1. Loss of nuclear p27kip1 is a frequent event in human RCCs and is a powerful predictor of poor outcome which, in combination with low DG expression, could help to identify high‐risk patients with clear cell RCC. (Cancer Sci 2010; 00: 000–000)