Background: Large cohort studies have reported no relationship between dietary fat and nonmelanoma skin cancer (NMSC), although a low-fat diet intervention reduced NMSC risk in a small clinical trial. In animal studies, skin tumor development has been reduced by low-fat diet. We evaluated the effect of a low-fat dietary pattern on NMSC and melanoma in the Women's Health Initiative Dietary Modification trial. Methods: Postmenopausal women aged 50 to 79 years (n = 48,835) were randomly assigned to the low-fat dietary pattern intervention (n = 19,541) or comparison group (n = 29,294). The intervention goals included decreasing fat intake to 20% or less of calories, increasing vegetable and fruit intake, and increasing grain intake. Self-reported incident NMSC (n = 4,907) and physician-adjudicated incident melanoma (n = 279) were ascertained every 6 months. Results: Over 8.1 years of follow-up, the low-fat diet intervention did not affect overall incidence of NMSC [HR 0.98; 95% confidence interval (CI), 0.92-1.04] or melanoma (HR, 1.04; 95% CI, 0.82-1.32). In subgroup analyses of melanoma risk, baseline fat intake interacted significantly with group assignment (Pinteraction = 0.006). Amongwomen with higher baseline fat intake, the dietary intervention significantly increased risk (HR, 1.48; 95% CI, 1.06-2.07), whereas, among women with lower baseline fat intake, the intervention tended to reduce melanoma risk (HR, 0.72; 95% CI, 0.50-1.02). Conclusions: In this large randomized trial, a low-fat dietary pattern did not affect overall incidence of NMSC or melanoma. Impact: A low-fat diet does not reduce incidence of NMSC, but an interaction between baseline fat intake and dietary intervention on melanoma risk warrants further investigation. © 2013 AACR.