Coffee drinking has been reported to have beneficial effects on insulin resistance, which has been directly associated with endometrial cancer. Although a relationship between coffee consumption and endometrial cancer risk is biologically plausible, this hypothesis has been previously explored in only 2 prospective studies, with a small number of cases. We used data from the Swedish Mammography Cohort, a population-based prospective cohort study of 60,634 women. During 17.6 years of follow-up, 677 participants were diagnosed with incident endometrial cancer (adenocarcinoma). We examined the association between self-reported coffee consumption (at baseline 1987-90 and in 1997) and endometrial cancer risk using Cox proportional hazards models. Each additional cup (200 g) of coffee per day was associated with a rate ratio (RR) of 0.90 [95% confidence interval (CI), 0.83-0.97]. In women drinking 4 or more cups of coffee a day, the RR for the risk reduction of endometrial cancer was 0.75 (95% CI, 0.58-0.97) when compared with those who drank 1 cup or less. The association seemed largely confined to overweight and obese women, who showed a respective risk reduction of 12% (95% CI, 0-23%) and 20% (95% CI, 7-31%) for every cup of coffee, but was not observed among normal-weight women. There was a statistically significant interaction between coffee consumption and body mass index (p(interaction) < 0.001). These data indicate that coffee consumption may be associated with decreased risk of endometrial cancer, especially among women with excessive body weight. If confirmed by other prospective studies, these results are of major public health significance.