Background: TNF‐Related Apoptosis Inducing Ligand (TRAIL) is a promising agent for the induction of apoptosis in neoplastic tissues. Important determinants of TRAIL sensitivity are two intracellular proteins of the TRAIL pathway, caspase‐8 and its anti‐apoptotic competitor cellular Flice‐Like Inhibitory Protein (cFLIP). Methods: The aim of this study was to investigate basic expression of caspase‐8 and cFLIP in normal colorectal epithelium (n = 20), colorectal adenomas (n = 66) and colorectal carcinomas (n = 44) using immunohistochemistry performed on both sporadic and Hereditary Non‐Polyposis Colorectal Cancer (HNPCC or Lynch syndrome)‐associated adenomas and carcinomas. Results: Expression of both caspase‐8 and cFLIP was similar in cases with sporadic and hereditary origin. Expression of caspase‐8 in colorectal adenomas and carcinomas was increased when compared to normal colon tissue (P = 0.02). Nuclear, paranuclear as well as cytoplasmic localizations of caspase‐8 were detected. Immunohistochemistry revealed an upregulation of cFLIP in colorectal carcinomas in comparison to normal epithelium and colorectal adenomas (P < 0.001). A large variation in the caspase‐8/cFLIP ratio was observed between the individual adenomas and carcinomas. Conclusion: Caspase‐8 and cFLIP are upregulated during colorectal carcinogenesis. Upregulation of caspase‐8 and/or downregulation of cFLIP may be interesting approaches to maximize TRAIL sensitivity in colorectal neoplasms.