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Cytokeratin (CK)18 is a useful serum biomarker for the determination of cell death of epithelial-derived tumors (carcinomas). ELISAs are available for caspase-cleaved CK18 (M30) released from apoptotic cells, or total CK18 (M65) released by cells undergoing cell death by any cause. These assays have been demonstrated to have prognostic or predictive utility in various types of carcinomas. Encouraging data have been reported by different investigators with regard to the potential use of CK18 as a serum efficacy biomarker for monitoring therapy efficiency in carcinoma patients. The ratio of caspase-cleaved to total CK18 can be determined conveniently in serum or plasma using commercially available ELISA kits (M30-Apoptosense® and M65® ELISA, Peviva AB, Bromma, Sweden). M30:M65 ratios potentially provide information as to whether tumor cells undergo apoptosis or necrosis. However, as discussed in this review, M30:M65 ratios should be interpreted with caution and, preferably, only be applied to samples that contain significant levels of CK18. We conclude that M30 and M65 biomarkers provide both quantitative and qualitative information on carcinoma cell death.