PURPOSE: Renal cell carcinoma (RCC) is the most lethal among the common urologic malignancies, comprising 3% of all human neoplasias; approximately 40% of patients eventually die of cancer progression. One third of patients who present with metastatic disease and up to 40% treated for localized disease generally experience recurrence. RCCs are characterized by high resistance to chemo-, radio- and immunotherapy. We recently discovered an endogenous enzymatic activity, which is particularly expressed in tumorigenic cell, endogenous non-telomerase reverse transcriptase (RT) of retrotrasposon / retroviral origin, as a specific target to induce proliferation arrest in a number of human carcinogenesis in vitro culture cell lines. METHODS: To address this possibility, we have employed RCC primary cell culture testing pharmacological inhibition, in vitro, by two characterized non nucleosidic RT inhibitors, nevirapine and efavirenz; next, we assessed morphological effects and analyzed putative modulation on gene expression profile. RESULTS: Both treatments reduced cell proliferation rate and induced morphological differentiation and gene expression reprogramming in different RCC analyzed tumor biomarkers. CONCLUSION: In this study we describe a new potential therapeutic approach to obtain considerable future benefits in renal carcinoma cure and attempt to establish a new possible pharmacological therapy based on oral drugs administration in renal RCC treatment.