Despite the increasing world-wide popularity of contraceptive intra-uterine devices (IUDs), their potential long-term effects on the risk of developing endometrial carcinoma have been poorly studied. This paper reports on the relationship between intra-uterine contraception and endometrial cancer by analyzing epidemiological data from a large, multicenter, population-based, case-control study of epithelial endometrial cancer. Cases were 437 women, 20 to 54 years of age, with histologically confirmed epithelial endometrial cancer ascertained through 6 population-based cancer registries in the United States. Controls were 3200 women selected at random from the populations of these areas. The age- and parity-adjusted odds ratio (OR) for the association between ever having used intra-uterine contraception and endometrial cancer was 0.51 (95% confidence interval (CI) 0.3-0.8). Although the protective effect increased with duration of use, a dose-response relationship among users was not statistically demonstrable. The association did not vary significantly with age at first or last IUD use or with time elapsed since first or last IUD use. Years of education significantly modified the effect of intra-uterine contraception. Thus, intra-uterine contraception appeared to be strongly protective for women with at least 13 years of education (OR = 0.29, 95% CI, 0.15-0.6). It is proposed that intra-uterine contraception exerts its protective effect through local structural and biochemical changes in the endometrium that may alter endometrial sensitivity and response to circulating estrogen and progesterone.