Endometrial cancer remains an important cause of morbidity and mortality in the United States, and recent genetic evidence supports the hypothesis that hormonal dysregulation is not the only important risk factor for this tumor. This multicenter, population-based case-control study investigated familial aggregation of endometrial cancer and other cancers. Cases were 455 women 20-54 years of age diagnosed with histologically confirmed primary epithelial carcinoma of the endometrium. Controls consisted of 3216 women 20-54 years of age identified by random-digit dialing. Family histories of cancer in female relatives were obtained by interview of cases and controls. Endometrial cancer in a first-degree female relative increased the risk of endometrial cancer by nearly 3-fold [odds ratio (OR), 2.8; 95% confidence interval (CI), 1.9-4.2]. Cases also reported significantly more colorectal cancer in family members than did controls (OR, 1.9; 95% CI, 1.1-3.3). Family history of cancer of the cervix, lung, ovary, and thyroid was not significantly associated with endometrial cancer, and breast cancer was not related unless more than one relative was affected. Family history of endometrial cancer is an independent risk factor for cancer of the endometrium. In addition, the observed association with a family history of colorectal cancer suggests that genes important in familial colorectal cancer may have substantial implications for endometrial cancer. Nearly 5% of incident endometrial cancer among women between the ages of 20 and 54 may be attributable to a family history of endometrial cancer, and 2% may be related to colorectal cancer.