Endometrial cancer is the most common female reproductive cancer in the United States. Most known risk factors for endometrial cancer are either genetic or related to exposure to estrogens; less is known about risk due to environmental exposures. While several studies have examined the relationship between perineal powder use and ovarian cancer risk, only one study has addressed the relationship with endometrial cancer risk. The Women's Health Initiative Observational Study, a prospective cohort study of 93,676 United States postmenopausal women from 1993-2005, measured perineal powder use at baseline via self-report. Cases of endometrial cancer were self-reported and confirmed by both local and central physician adjudicators. Cox proportional hazards regression was used to examine the association between perineal powder use and endometrial cancer, adjusting for known risk factors. Of the 48,912 women in our analysis, 25,181 (52%) reported ever use of perineal powders. There were 452 incident cases of endometrial cancer diagnosed during 366,872 person-years of follow-up. Ever use of perineal powder was not significantly associated with increased risk of endometrial cancer (hazard ratio 1.05, 95% confidence interval 0.87-1.27). However, use of any perineal powder for 20 or more years was associated with a 30% increase in risk (hazard ratio 1.30, 95% CI 1.01-1.67) compared to never users. Use of powder on both a diaphragm and the perineal area was associated with a 39% increase in risk (hazard ratio 1.39, 95% CI 1.00-1.93). Cessation of perineal powder use, particularly on a diaphragm, may help reduce risk of endometrial cancer.