The need for effective targeted therapies for renal cell carcinomas (RCCs) has fueled the interest for understanding molecular pathways involved in the oncogenesis of kidney tumors. Aiming to analyze the expression status and prognostic significance of mTOR and hypoxia-induced pathway members in patients with clear cell RCC (ccRCC), tissue microarrays were constructed from 135 primary and 41 metastatic ccRCCs. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome. PTEN levels were significantly lower in primary and metastatic ccRCCs compared with benign tissues (P<0.001). Levels of phos-AKT, phos-S6, and 4E-binding protein-1 (4EBP1) were higher in metastatic ccRCC (P≤0.001). For phos-S6 and 4EBP1, levels were higher in primary ccRCC compared with benign tissues (P<0.001). c-MYC levels were higher in metastatic ccRCC (P<0.0001), and incremental p27 levels were observed in benign, primary ccRCC, and metastatic ccRCC (P<0.0001). HIF-1α levels were significantly higher in primary and metastatic ccRCCs compared with benign tissues (P<0.0001). In primary ccRCC, levels of all mTOR and hypoxia-induced pathway members were significantly associated with pT stage (P≤0.036), p27 levels with Fuhrman grade (P=0.031), and 4EBP1, p27, and HIF-1α levels with tumor size (P≤0.025). Tumor size, HIF-1α, and phos-S6 levels were associated with disease-specific survival (DSS) (P≤0.032) and tumor progression (P≤0.043). In conclusion, both mTOR and hypoxia-induced pathways were activated in primary and metastatic ccRCC. PTEN loss seems to be an early event during tumorigenesis. Tumor size, HIF-1α, and phos-S6 expression were found to be independent predictors of both DSS and tumor progression in primary ccRCC. © 2011 by Lippincott Williams & Wilkins.