Objective To investigate the prevalence of cellular FLICE-like inhibitory protein (cFLIP) alterations in colorectal cancer and their possible implications for the progression of colorectal cancer. Methods The long type cFLIP (cFLIPL) was examined in 43 colorectal cancer specimens and the matched normal colorectal specimens by immunohistochemistry. Immunohistochemical staining for cFLIPL was assessed on an arbitrary semi-quantitative scoring system. Stained cells were counted under the magnification field (×100) and at least 20 fields per case were examined. Fields with non-stained cells were scored 0; fields with stained cells less than 5% were scored 1; fields with stained cells from 5% to 25% were scored 2; fields with stained cells between 26% and 50% were scored 3; and fields with stained cells more than 50% were scored 4. According to the above schedule， a mean score of each specimen was calculated. Results cFLIPL protein expressions of variable intensity and extent were detected in the normal colorectal mucosa and adenocarcinomas. cFLIPL was mainly expressed in the cytoplasma. The positive cells were distributed in diffuse manner. The mean expression score in normal mucosa ranged from 0 to 2.95 (mean score: 1.55±0.86); 4.7%(2/43) of all cases were unstained and 20.9%(9/43) showed a weakly stained pattern (0＜mean score≤1); 74.4%(32/43) of all cases were positively stained (1.00＜mean score≤2.95), respectively. cFLIPLprotein was expressed in all adenocarcinomas and the score ranged from 0.80-4.00 (mean score: 3.06±0.75); 62.8% (27/43) of the tumors examined were predominantly cFLIPL positive (mean score ＞3), 34.9%(15/43) of the tumors were cFLIPLpositive (1＜mean score ≤3) and only one case was cFLIPL weakly positive (score: 0.80). 72.1% (31/43) of adenocarcinomas expressed cFLIPLmore intensely and extensively than matched normal colonic mucosa. cFLIPL expression of colorectal cancer was significantly higher than that of matched normal mucosa, which was statistically significant (P＜0.01). The extent of cFLIPL expression in tumors was independent of Dukes stage, tumor stage, gross type of tumor, histological type, or lymph and hepatic metastasis. Conclusion The expression level of cFLIPL in adenocarcinomas is much higher than that in matched normal mucosa. Overexpression of cFLIPL is a tumor-specific phenomenon, which can provide a selective growth advantage for colorectal cancer cells to escape from death receptor-mediated apoptosis.