Members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at a much higher rate, and at a much younger age, than the general population. To quantify lifetime colorectal cancer risk in HNPCC family members, we calculated the cumulative incidence (CI) in different age categories, and compared this to the general population. Furthermore, we investigated whether successive generations of HNPCC families had earlier onset of disease. In 51 HNPCC families, selected according to the ''Amsterdam criteria'', the CI of colorectal cancer at age 75 was 40%, compared to only 4% in the general population. The CI ratio (CIR) of HNPCC family members relative to the general population was 148 at age 40, 79 at age 50 and 11 at age 75. Comparing successive generations of HNPCC families, the CI at age 75 increases from 19% in the ancestors to 32% in the first generation and 55% in the second generation. However, Cox proportional hazard analysis showed that this generation effect (RR per generation: 1.8, 95% CL 5 1.4-2.2) largely disappears after adjustment for year of birth. In summary, at young ages, HNPCC family members experience an up-to-150 times higher risk for colorectal cancer than the general population. This risk difference declines from age 60 onwards. The earlier age of onset in successive HNPCC generations does not appear to be a biological feature of HNPCC, but reflects a secular time trend in cancer occurrence in these families, similar to that in the general population.