Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and antibodies against TRAIL receptors death receptor 4 (DR4) and death receptor 5 (DR5) are under investigation for cancer therapy. To study the potential application of these agents, the expression of DR4 and DR5 were studied immunohistochemically in colorectal adenomas and carcinomas from patients with sporadic disease (n=74 and 56, respectively), familial adenomatous polyposis (FAP, n=41 and 4, respectively) and hereditary non-polyposis colorectal cancer (HNPCC, n=50 and 21, respectively). BAX, which is frequently mutated in tumours with high-frequency microsatellite instability (MSI-H) may play a role in sensitivity to TRAIL. Therefore, MSI-H carcinomas (n=42, of which 27 sporadic and 15 HNPCC) were analysed for apoptotic activity, assessed by M30 immunoreactivity, and BAX mutations. Most adenomas from all three patient groups expressed DR4 and DR5. Most carcinomas expressed DR4, except for six cases, all with mucinous histology. All carcinomas, including mucinous carcinomas, showed DR5 expression. BAX mutations were found in 6/42 MSI-H cancers with similar apoptotic indices and expression of DR4, DR5 and TRAIL in BAX mutant and wild-type cases. Since most sporadic and hereditary colorectal neoplasms express DR4 and DR5, targeting of these receptors may be a potential prevention or treatment strategy.