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Introduction: Diverticulitis is a significant cause of morbidity among older women, and little attention has been paid to understanding its etiology. We have shown that menopausal hormone therapy (MHT) is associated with the risk of inflammatory bowel disease. In this study, we prospectively examined the association between MHT and the risk of incident diverticulitis. Methods: We studied 65,367 postmenopausal women enrolled in the Nurses' Health Study who provided detailed information on hormone use and other medical and lifestyle factors biennially, and on diet every 4 years. Between 2008 and 2014, participants reported any episodes of diverticulitis that required antibiotics and the date of occurrence. We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Over 24 years encompassing 1,297,165 person-years of follow-up, we documented 5,425 incident cases of diverticulitis. We observed an increased risk of diverticulitis among both current (HR 1.28; 95% CI 1.18–1.39) and past (HR 1.35; 95% CI 1.25–1.45) MHT users compared to never users. The increased risk was observed among participants using estrogen only (HR 1.30; 95% CI 1.20–1.41) and those using combined estrogen and progesterone (HR 1.31; 95% CI 1.21–1.42) compared to nonusers. The risk did not increase with longer duration of use (P-trend = 0.76). The association between MHT and diverticulitis was not modified by age, body mass index, past oral contraceptive use, or fiber intake (all P-interaction >0.11). Conclusions: Menopausal hormone therapy was associated with an increased risk of diverticulitis. Further studies are needed to understand the potential mechanisms that may underlie this association. [ABSTRACT FROM AUTHOR]