Context: The mean body weight of US adults increased by 3.6 kg (7.6 lb) during the past 15 years, but few studies exist that examine the impact of such weight change on functional health status. Objective: To investigate, prospectively, the association between weight change and health-related quality of life in women. Design and Setting Nurses' Health Study, a 4-year prospective observational study from 1992 to 1996, using the Medical Outcomes Study Short-Form 36 Health Status Survey (a self-administered 36-item questionnaire) to measure quality of life. Participants: A cohort of 40098 women (from 46-71 years old in 1992) grouped according to 3 patterns of weight change over the 4-year period: women whose weight remained within 2.25 kg (5 lb) of their baseline weight, women who lost 2.25 kg (5 lb) or more, and women who gained 2.25 kg (5 lb) or more. Main Outcome Measures: Change in scores on 7 health-related quality-of-life dimensions: physical functioning, vitality, bodily pain, limitations in role functioning due to emotional or physical problems, social functioning, and mental health, measured by the Short-Form 36 Health Status Survey. Results: A total of 15 602 women (39%) maintained their weight, 15 160 (38%) gained between 2.25 and 9.0 kg (5-20 lb), and 6667 (17%) lost between 2.25 and 9.0 kg (5-20 lb). Weight gain was associated with decreased physical function and vitality, and increased bodily pain regardless of baseline weight. For example, the odds ratio for developing role limitations due to physical problems was 2.05 (95% confidence interval, 1.69-2.49) for the leanest women who gained 9.0 kg (20 lb) or more. Weight loss in overweight women was associated with improved physical function and vitality as well as decreased bodily pain. Weight change was more strongly associated with physical rather than mental health. The impact of weight change, especially weight gain, was just as strong in women 65 years and older as in women younger than 65 years. Conclusions: These longitudinal data support current US guidelines for women of all body mass index levels to avoid weight gain. Weight maintenance and, in cases of overweight, weight loss are desirable and likely to be beneficial for physical function, vitality, and bodily pain.