Resistance to anticancer drugs is often observed in prostate cancer therapy. Kindlin-2 was recently found overexpressed during cancer progression. In this study, we examined the functional role of Kindlin-2 in cisplatin-induced prostate cancer cell death. Kindlin-2 was highly expressed in the androgen-insensitive (PC-3 and DU-145), but not in the androgen-sensitive cell lines (e.g., LNCaP). Overexpression of Kindlin-2 in LNCaP protected the cells from cisplatin-induced death, while Kindlin-2 knock-down in PC-3 cells enhanced cisplatin sensitivity. Mechanistically, Kindlin-2 regulation of the anti-apoptotic Bcl-xL may explain the increased cell death in the absence of Kindlin-2. Taken together, Kindlin-2 appears to play a functional role in prostate cancer cell sensitivity to cisplatin. Targeting Kindlin-2 may therefore improve drug efficacy and reduce drug doses, and would likely be beneficial for the treatment of prostate cancer.