The Ran small GTPase (Ran) is involved in the regulation of nuclear transport, microtubule nucleation and dynamics, and spindle assembly. To address the question of whether Ran protein is associated with the progression of renal cell carcinoma (RCC), we compared by Western blotting the Ran protein levels in surgical RCC specimens from 180 consecutive Japanese patients with those in the corresponding nontumor tissue from the same patient. We also examined the Ran protein levels in tumors of different grades and stages. Ran proteins were more abundant in RCC tumor tissues than in nontumor tissues (p < 0.0001). High Ran expression was associated with higher grade, local invasion, and metastasis (p < 0.0001). Kaplan-Meier plots linked high Ran protein expression to a shorter overall survival in all cases (p < 0.0001) and a shorter disease-free survival in those without metastasis at radical or partial nephrectomy (M0; 131 cases, p < 0.0001). Ran protein expression was an independent factor influencing overall survival univariate analysis (p < 0.0001) and disease-free survival by multivariate analysis (p < 0.05). Our findings suggest that Ran is associated with the progression of RCC. © 2008 Wiley-Liss, Inc.