The occurrence of multiple primary malignant neoplasms characterizes virtually all varieties of hereditary cancer. This report focuses on this phenomenon in 11 families with the Cancer Family Syndrome (heritable adenocarcinomas of the colon and endometrium) and a single extended kindred with site-specific colon cancer. Of the 316 relatives with cancer in the 12 families, 68 (21.5%) had two or more primary malignancies and 59 (86.8%) of these multiple primaries involved the colon and/or endometrium. A pooled analysis of this resource revealed a consistent 3% risk for a second primary cancer in each year of survival following first onset. If a second primary occurs, the risk for a third is extremely high (6.9% per year), but shows a nonlinear trend with increasing survival following second onset. The high risk for development of extraprimary malignancies in patients from these kindreds indicates that careful consideration should be given to total removal of their principal target organs following the initial manifestation of cancer.