BACKGROUND Macronutrients such as fat and fiber have been hypothesized to play a role in the etiology of endometrial cancer. METHODS To investigate these associations, the authors analyzed data from the Nurses' Health Study. From 1980 to 2006, 669 invasive adenocarcinoma cases were identified over 1.3 million person-years of follow-up. Dietary intake was assessed in 1980 and updated every 2-4 years. Cox proportional hazard models were used to calculate relative risks (RRs), controlling for total energy and other risk factors. RESULTS Overall, the authors found no significant associations between most dietary factors and endometrial cancer risk. Total fat was associated with a borderline significant decreased risk (top vs. bottom quintile RR = 0.78; 95% CI = 0.60-0.99; P(trend) = 0.18). Findings for animal fat were similar. No inverse associations between dietary fibers and cancer risk were observed. Cereal fiber was modestly positively associated with risk (top vs. bottom quintile RR = 1.38, 95% CI = 1.07-1.79; P(trend) = 0.05). The inverse association with animal fat intake and a positive association with carbohydrate intake were observed among premenopausal but not among postmenopausal women. CONCLUSIONS In this large prospective study, no overall association was observed between dietary fat, fiber, and carbohydrates with endometrial cancer risk, although several of the relationships may vary by menopausal status. CONCLUSIONS Dietary fat and fiber intake do not seem to play a major role in endometrial cancer etiology overall. However, further evaluation of these associations, particularly in premenopausal women, is needed.