BACKGROUND: Decreased fat intake with weight loss and increased exercise may reduce the risk of diabetes mellitus in persons with impaired glucose tolerance. This study was undertaken to assess the effects of a low-fat dietary pattern on incidence of treated diabetes among generally healthy postmenopausal women. METHODS: A randomized controlled trial was conducted at 40 US clinical centers from 1993 to 2005, including 48,835 postmenopausal women aged 50 to 79 years. Women were randomly assigned to a usual-diet comparison group (n = 29,294 [60.0%]) or an intervention group with a 20% low-fat dietary pattern with increased vegetables, fruits, and grains (n = 19,541 [40.0%]). Self-reported incident diabetes treated with oral agents or insulin was assessed. RESULTS: Incident treated diabetes was reported by 1303 intervention participants (7.1%) and 2039 comparison participants (7.4%) (hazard ratio, 0.96; 95% confidence interval, 0.90-1.03; P = .25). Weight loss occurred in the intervention group, with a difference between intervention and comparison groups of 1.9 kg after 7.5 years (P < .001). Subgroup analysis suggested that greater decreases in percentage of energy from total fat reduced diabetes risk (P for trend = .04), which was not statistically significant after adjusting for weight loss. CONCLUSIONS: A low-fat dietary pattern among generally healthy postmenopausal women showed no evidence of reducing diabetes risk after 8.1 years. Trends toward reduced incidence were greater with greater decreases in total fat intake and weight loss. Weight loss, rather than macronutrient composition, may be the dominant predictor of reduced risk of diabetes.