We examined the association of percent energy intake from fat with subsequent weight change in 2580 men and 4567 women, using data from the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up Study (NHEFS). Weight change was defined as the difference between the follow-up weight (NHEFS, 1982-1984) and the baseline weight (NHANES I, 1971-1974). Fat intake was estimated from a 24-h dietary recall obtained at baseline. Regression analyses adjusted for potential confounders showed no significant association of percent fat energy with weight change in men. Among women aged < 50 y, the inverse relation of percent fat energy with weight change was significant (beta = -0.052, P = 0.04). After exclusion of respondents with any morbidity from the analytic cohort, percent fat energy and weight change were positively associated in men (beta = 0.046, P = 0.05), but not in women. In conclusion, percent fat energy intake and weight change were inversely related in women aged < 50 y in the NHEFS cohort, but positively associated in men without any morbidity.