Complex segregation analysis was conducted in a series of patients with hereditary non-polyposis colorectal cancer (HNPCC) ascertained through probands registered in the Cancer Registry of the Health Care District of Modena, Northern Italy. Altogether there were 125 nuclear families segregating for HNPCC, for a total of 672 individuals. The analysis favoured a two-locus model, with both susceptibility genes rare and dominant. The gene frequency of the deleterious allele at the major locus is estimated to be low qm=0·004 and for the second locus the estimate is even lower q=0·00003. Both genes defining the two-locus model seem to be highly penetrant. The lifetime penetrance of the abnormal gene at the major locus is estimated to be 0·73 for female, while the estimation for male is higher, 0·85.