To investigate the relationship between family history of cancer in first-degree relatives and the risk of endometrial cancer, we carried out a large multicentre case-control study in Italy between 1992 and 2006, including 454 endometrial cancer cases and 908 controls admitted in hospital for acute, non-neoplastic diseases. Conditional logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CI). Relative to women with no family history of uterine cancer, the ORs were 2.1 (95% CI: 0.7-6.4) for those reporting a family history of endometrial cancer and 1.8 (95% CI: 1.0-3.2) for a family history of any uterine cancer. A family history of intestinal cancer was directly associated with endometrial cancer risk (OR=1.6; 95% CI: 1.0-2.7). Direct associations were found for a few other cancer sites. In conclusion, a family history of endometrial, uterine or intestinal cancer in first-degree relatives is associated with an increased risk of endometrial cancer.