BACKGROUND The bluetongue virus (BTV) is the prototype virus in the genus Orbivirus within the family Reoviridae. Recent studies indicate that BTVs are capable of infecting and selectively lysing human hepatic carcinoma cells (Hep-3B) and prostate carcinoma cells (pc-3). This study was designed to evaluate the oncolytic potential of BTV in experimental models of human renal cancer in vitro and in vivo. MATERIAL AND METHODS Five human renal cancer cell lines, ACHN, CAKI-1, OS-RC-2, 786-O, and A498, were used in this study to analyze BTV replication. These cells were lysed by oncolysis compared to normal control. Xenograft models were used to assess the efficacy and toxicity of BTVs in vivo. Data were analyzed by one-way ANOVA or two-sided unpaired t tests. RESULTS The results showed HPTEC cells to be relatively resistant to cytotoxic effects of BTVs and exhibited normal growth rate even at high dose of BTVs. Nonetheless, the renal cancer cells showed a remarkably higher sensitivity to BTVs. Moreover, the ultramicroscopic subcellular changes were also detected in the renal cells. The viral particles were observed in all the RCC cell lines, but not in HPTEC cells. Intratumoral injections of BTVs significantly decreased the tumor volume as compared to animals that received no virus treatment. Infection with BTVs significantly increased the percentage of apoptotic renal cancer cells but not the HPTEC cells. Moreover, BTV triggered apoptosis in renal cancer cells via a mitochondria-mediated pathway. CONCLUSIONS This study for the first time demonstrated the oncolytic potential of BTV in experimental models of human renal cancer. BTV exhibits the potential to inhibit human renal cancer cell growth in vitro and in vivo.