Background-Despite the recent discovery of four genes responsible for up to 90% of all cases of hereditary non-polyposis colorectal cancer (HNPCC), there will still be families in whom predictive testing is not possible. A phenotypic biomarker would therefore be useful. An upwards shift of the proliferative compartment in colonic crypts is reported to be one of the earliest changes in premalignant mucosa. Aims-To assess the role of crypt cell proliferation as a phenotypic biomarker in HNPCC. Patients-Thirty five patients at 50% risk of carrying the HNPCC gene (21 of whom subsequently underwent predictive testing and hence gene carrier status was known) and 18 controls. Methods-Crypt cell proliferation was measured at five sites in the colon using two diVerent techniques. Labelling index was determined using the monoclonal antibody MIB1 and whole crypt mitotic index was measured using the microdissection and crypt squash technique. The distribution of proliferating cells within the crypts was also assessed. Results-There were no significant diVerences in the total labelling index or mean number of mitoses per crypt, nor in the distribution of proliferating cells within the crypt, between the study and control groups at any site. When the 21 patients in whom gene carrier status was known were analysed separately there were no significant diVerences in the measured indices of proliferation between the HNPCC gene carriers and non-gene carriers. Conclusion-Crypt cell proliferation is not a discriminative marker of gene carriage in HNPCC. (Gut 1998;43:85-92)