We examined whether there is an association between whole grain intake and incident endometrial cancer and whether the association varied by use of hormone replacement therapy. The study included 23,014 Iowa women, aged 55-69 years in 1986. A mailed food frequency questionnaire was used to estimate grain intake, hormone replacement therapy use, and other cancer risk factors. Cancer incidence from 1986 to 1998 was also collected. In analyses stratified by hormone replacement therapy use, an inverse association between whole grain intake and endometrial cancer was observed among never-users of hormone replacement therapy (p for trend = 0.05). Never-users in the highest quintile of whole grain intake were 0.63 times as likely to develop endometrial cancer as those in the lowest quintile of whole grain intake (95% confidence interval = 0.39-1.01). Among hormone replacement therapy users, no association between whole grain intake and endometrial cancer was evident. There was no statistically significant association between whole grain intake and incident endometrial cancer when users of hormone replacement therapy and nonusers were analyzed together. There also was no association between refined grain intake and endometrial cancer. Whole grain intake may protect against endometrial cancer among never-users of hormone replacement therapy.