OBJECTIVES Recommended treatment duration of atrophic vaginitis in postmenopausal women with vaginal estrogen (VE) is currently limited to 6-12 months, the length of clinical trials conducted to date, due to concerns of potential development of endometrial carcinoma. In practice, many women use VE longer. This study examines the association between VE use and risk of endometrial carcinoma over a 3 year follow-up period among Medicaid enrollees. METHODS A retrospective cohort study was conducted using North Carolina Medicaid prescription and medical claims between January 1998 and December 2007. The study included women ages 18-64 years with a prescription claim for VE (cream, tablet, and ring forms) or a diagnosis of atrophic vaginitis (identified by ICD-9 code 627.3). Demographic factors included age and race (African American, white, or other). Comorbidity risk adjustment was determined using the Charlson-Deyo method. Multiple logistic regression was performed to assess the association of VE use and endometrial carcinoma adjusting for age, race, and comorbidities. RESULTS A total of 770 patients prescribed VE (mean age 50.1 years +/- 8.4) and 881 patients diagnosed with atrophic vaginitis but not treated with VE (mean age 49.4 years +/- 9.8) were identified in the database. Ten cases of uterine carcinoma were identified among the VE patients; 11 cases among women not prescribed VE. Logistic regression results showed no significant difference in the occurrence of endometrial carcinoma between women on VE therapy and those not on VE therapy (OR=1.11, 95%CI: 0.47-2.65, P=0.814). Older age was the only significant predictor of uterine carcinoma (OR=1.11, 95%CI: 1.03-1.20, P=0.008); i.e., for a ten-year increase in age, odds of endometrial carcinoma increased by a factor of 2.8. CONCLUSIONS With three years of follow-up showed no association between VE exposure and endometrial carcinoma. Increasing age was found to be the only significant risk factor.