Clear-cell renal cell carcinoma is a highly treatment-resistant tumor type. Heme oxygenase-1 plays an anti-apoptotic role in cancer chemotherapeutic inducing tumor-progression. The miR-200 family was involved in the process of mesenchymal-epithelial transition (MET) during renal development. In the present study, we demonstrated the regulatory relationship between miR-200c and HO-1. We provided evidences to elucidate that miR-200c could sensitize ccRCC cells to sorafenib or imatinib to inhibit cell proliferation, at least partly by targeting HO-1. Moreover, the correlation between miR-200c and HO-1 expression level and drug resistance in ccRCC was also determined. Combined application with chemotherapeutic drugs, miR-200c, a HO-1 inhibitor, may enhance the efficiency of therapy by promoting both apoptosis and autophagy.