BACKGROUND & AIMS: An association between female hormones and symptomatic gastroesophageal reflux disease (GERD) and may be modified by obesity is suggested but not proven. Factors affecting GERD progression, however, are largely unknown. METHODS: At 40 US clinical centers, postmenopausal women with hysterectomy (n = 10,739) were randomly assigned to receive 0.625 mg/d of conjugated equine estrogens or placebo. Women without hysterectomy (n = 16,608) were randomly assigned to receive estrogen plus progestin, given as 0.625 mg conjugated equine estrogens/d plus 2.5 mg medroxyprogesterone acetate/d, or placebo. We performed secondary analyses using data from these trials. RESULTS: After 1 year, there was a trend toward a higher incidence of symptomatic GER among women randomly assigned to the estrogen treatment (4.2%) than with placebo (3.1%). The estrogen plus progestin treatment did not affect this risk. Neither treatment affected the progression of existing GER symptom. There was a dose-response association between baseline obesity, particularly as measured by waist circumference, with more than double the risk of incident symptomatic GER at 1 year among women with the largest waist circumference (>or=114 cm) compared with a normal waist circumference (70-80 cm). Weight gain at 1 year was associated with elevated risk of incident symptomatic GER. Weight loss at 1 year alleviated existing GER symptoms. No interaction between hormone therapy and obesity on symptomatic GER was observed. CONCLUSIONS: Estrogen treatment alone, but not with progestin, may cause GER symptoms in postmenopausal women. Increasing weight and girth increases the risk of developing GER symptoms, whereas weight loss alleviates existing GER symptoms. This trial was registered at www.clinicaltrials.gov as NCT00000611.