The aggregation of colon, endometrial, ovarian, and possibly breast cancers in families has been described as a "cancer family syndrome" (now called Lynch syndrome II). To determine if the familial clustering of these malignancies was more common in women with cancer than without, we analyzed data from the Iowa Women's Health Study (IWHS), a population-based sample of 41,837 women aged 55-69 years. Self-reported information was collected on history of colon, uterine, ovarian, and breast cancers in female first-degree relatives. A family history of cancer of the breast (odds ratio [OR] = 1.4), colon (OR = 1.3), and uterus (OR = 1.3), but not ovary (OR = 1.2), was significantly more common among women with a personal history of any of these four cancers (all P < 0.05); the pattern of the ORs suggested strongly that the clustering tended to be site-specific. Age-adjusted relative risks (RR) of incident colon cancer over 5 years of follow-up (N = 237) were calculated with regard to family history. Colon cancer incidence was increased among women with a family history of breast (RR = 1.3), uterine (RR = 1.4), colon (RR = 1.5), and ovarian (RR = 1.3) cancers, although none of the risk estimates achieved statistical significance. RR was, however, significantly related to the number of different cancer sites reported among family members (Ptrend = 0.008). These data on a representative sample of postmenopausal women suggest that family histories of colon, breast, uterine, and ovarian cancers are associated with an increased risk of cancer at the same site, but provide little support for the hypothesis that Lynch syndrome II is a non-random occurrence.