<p>Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and exploration of its molecular mechanism benefits for developing more effective molecular targeted drugs. CDC6 has been found to be highly expressed in a variety of malignancies and plays oncogenic role; however, its function in ccRCC has not been elucidated. In this work, immunohistochemical (IHC) staining was used to detect protein expression of genes in clinical tissues. qPCR and WB were used for expression detection of mRNA and protein levels in cells. The Celigo assay, plate cloning assay, flow cytometry, and wound-healing/Transwell assays were used to detect cell proliferation, colony formation, apoptosis, and migration, respectively. A subcutaneous xenograft model in nude mice was used to verify the function of CDC6 in vivo. The results of clinical sample-related detection as well as analysis showed that CDC6 was highly expressed in ccRCC and was significantly associated with higher tumor malignancy as well as worse patients’ prognosis. Knockdown of CDC6 in ccRCC cells significantly inhibited cell proliferation and migration while promoting apoptosis, and inhibited in vivo growth of transplanted tumors in animal models. Mechanistically, RRM2 is identified as a potential downstream effector molecule that has co-expression characteristics with CDC6 and whose expression levels are regulated by it. More importantly, RRM2 knockdown mediated tumor suppression could partially reversed CDC6 overexpression induced tumor promotion. This study identified CDC6/RRM2 axis as a potential target for development of novel targeted therapy for ccRCC treatment.</p>