HNPCC is an inherited disorder characterized by an increased risk for cancers of the colorectum and endometrium. An increased risk of cancer of other organs, and heterogeneity among HNPCC families in extracolonic cancer risk, has been hypothesized. We evaluated these hypotheses in a study of 1317 high risk members of 23 HNPCC families. Expected numbers of cancer occurrences were calculated from general population incidence data, and compared to observed numbers. The distribution of cancers among families was compared to the distribution expected under the hypothesis of uniform risk. Significant excesses of cancers of the stomach, small bowel, hepatobiliary system, upper urologic tract, and ovary were found. Gastrointestinal tract cancers were uniformly distributed among families, but urologic tract and gynecologic tract cancers were significantly heterogeneously distributed. Our results indicate that HNPCC family members are at increased risk for cancer at specific extracolonic sites. We also found evidence of heterogeneity among HNPCC families in the risk for some extracolonic cancers.