Patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC) develop microsatellite-unstable colorectal cancers that tend to be more proximally located and are histologically more likely to show high numbers of tumor-infiltrating lymphocytes, a lack of dirty necrosis, mucinous or poor differentiation, and a Crohn-like host immune response, when compared with microsatellite-stable cancers. However, histologic features that are characteristic of and can perhaps distinguish colorectal adenomas in HNPCC patients from those occurring in the general population have not been previously reported. We compared 16 adenomas endoscopically removed from patients with genetically proven HNPCC to 32 control adenomas, group-matched for patient age and sex, along with endoscopic size, shape, anatomic location, and presence of high-grade dysplasia. Adenomas from HNPCC patients were more likely to contain high numbers of adenoma-infiltrating lymphocytes (AILs) with 12 of 16 (75%) adenomas having >or=5 AILs per high-power field (HPF) as opposed to 4 of 32 (12%) adenomas in the control group (P=0.00003). HNPCC adenomas were also less likely to contain increased numbers of apoptotic bodies: 7 of 16 (44%) contained >or=5 apoptoses per HPF, compared with 27 of 36 (84%) control adenomas (P=0.006). The presence of necrosis or serrated architecture, percent villous component, and numbers of mitotic figures per HPF did not differ significantly between the 2 groups. Therefore, increased numbers of AILs and decreased numbers of apoptoses in colorectal adenomas are simple and inexpensive markers that raise the possibility of HNPCC.