In the present study, we investigated whether the upregulation of miR-21 expression is a predictor of advanced clinicopathological features and poor prognosis in patients with renal cell carcinoma (RCC). It was found that the expression of miR-21 not only had a significant effect on the clinicopathological features and survival in patients with RCC, but also exerted an important influence on the occurrence rate of RCC. In addition, miR-21 expression was lower in the human kidney HRPTEpiC cell line than that noted in RCC A-498 cells. Meanwhile, the overexpression of miR-21 not only increased cell proliferation, inhibited apoptosis and reduced caspase-3 activity in the A-498 cells, but also suppressed p53, CDKN1A p21, cyclin E2 and Bax protein expression in the A-498 cells. In contrary, the downregulation of miR-21 expression promoted the protein expression of p53, CDKN1A p21 and cyclin E2, and decreased Bax protein expression and caspase-3 activity in the A-498 cells. Our data indicate a clear correlation between miR-21 expression and clinicopathological features and poor prognosis in patients with RCC through the p53/p21-cyclin E2-Bax/caspase-3 signaling pathway.