Cysteine-rich 61 (CYR61), a member of the connective tissue factor CCN (Cyr61, CTGF, Nov) family, facilitates angiogenesis by interacting with integrins. Recent observations have indicated that CYR61 also rescues cells from anti-cancer drug-mediated apoptosis but the detailed mechanism underlying the role of CYR61 during apoptosis has not been identified. To better understand the role of CYR61 during cisplatin-induced apoptosis in tumor cells, we overexpressed or inhibited CYR61 expression in human cervical cancer cells (HeLa cells) and measured cisplatin-mediated apoptosis. The results from these experiments clearly demonstrate that CYR61 prevents cisplatin-induced apoptosis by inhibiting caspase-3 activity in HeLa cells. Therefore, CYR61 may be a useful therapeutic target for cisplatin-resistant tumors.