OBJECTIVE: To evaluate the relationship between change in weight and pelvic organ prolapse (POP) progression/regression in women during a 5-year period. METHODS: Postmenopausal women with uteri (N=16,608), ages 50 to 79, who were enrolled in the Women's Health Initiative (WHI) Estrogen plus Progestin Clinical Trial between 1993 and 1998 were included in this secondary analysis. Baseline pelvic examination, repeated annually, assessed uterine prolapse, cystocele, and rectocele using the WHI Prolapse Classification System. Statistical analyses included univariate and multiple logistic regression methods. RESULTS: During the 5-year time period, the majority of women (9,251, 55.7%) gained weight (mean 4.43 kg, +/-5.95 kg), and the overall rate of prolapse (WHI Prolapse Classification System: grades 1-3) increased from 40.9% at baseline to 43.8% at year 5 of evaluation. Controlling for age, parity, race, and other health/physical variables, being overweight (body mass index [BMI] between 25 and 29.9) or obese (BMI of at least 30) at baseline was associated with progression in cystocele, rectocele, and uterine prolapse compared with women with healthy BMIs (BMI is calculated as weight (kg)/[height (m)]). Specifically, the risk of prolapse progression in overweight and obese women as compared with the participants with healthy BMIs increased by 32% and 48% for cystocele, by 37% and 58% for rectocele, and by 43% and 69% for uterine prolapse, respectively. Adjusting for women with prolapse at baseline and baseline BMI, a 10% weight change was associated with minimal change in overall POP. Specifically, a 10% weight loss was associated with a borderline worsening of uterine prolapse (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.88-0.97) and a minimal regression of cystocele (OR 1.03, 95% CI 1.00-1.05) and rectocele (OR 1.04, 95% CI 1.01-1.07). CONCLUSION: Being overweight or obese is associated with progression of POP. Weight loss does not appear to be significantly associated with regression of POP, suggesting that damage to the pelvic floor related to weight gain might be irreversible. LEVEL OF EVIDENCE: II.