Silibinin as an effective anti-cancer and chemopreventive agent in various epithelial cancer models has been reported inhibition of cancer cell growth through mitogenic signaling pathways. However, whether it could inhibit renal cell carcinoma growth and what are the underlying mechanisms is still not well elucidated. Since EGFR-MAPK and apoptosis pathways play important roles in renal cell carcinoma survival. Here, for the first time we evaluated the inhibitory proliferation effects of silibinin in renal cell carcinoma growth and examined whether silibinin modulates EGFR-MAPK and tumor apoptosis cascades signals. Our results indicated that silibinin effectively inhibits the renal cancer carcinoma Caki-1 cell proliferation and induces apoptosis through inhibiting the activation of EGFR and ERK and the expression of survivin, up-regulating the expression of p53 and triggering the cascades of caspase pathways. Our results suggested silibinin might be as one of the candidate chemopreventive agents for renal cell carcinoma therapy.