Purpose: Vasomotor hot flashes are a common problem in menopausal women. Given concerns regarding estrogen and/or combined hormonal therapy, other treatment options are desired. Prior trials have confirmed that progestational agents and newer antidepressants effectively reduce hot flashes. This current trial compared a single intramuscular dose of medroxyprogesterone acetate (MPA), depot preparation, versus daily oral venlafaxine as treatment for hot flashes. Methods: Women with bothersome hot flashes were entered onto this trial, were randomly assigned to treatment, and then had a baseline week where hot flash scores were recorded without treatment. They were then treated and observed for 6 weeks; daily diaries were used to measure hot flash frequencies and severities. There were 109 patients per each arm randomly assigned to receive MPA 400 mg intramuscularly for a single dose versus venlafaxine 37.5 mg per day for a week, then 75 mg per day. Results: During the sixth week after random assignment, hot flash scores were reduced by 55% in the venlafaxine arm versus 79% in the MPA arm (P < .0001). In an intention-to-treat analysis, 46% of venlafaxine patients (50 of 109) compared with 74% of the MPA patients (81 of 109) had a decrease in hot flashes by more than 50% from baseline (P < .0001). Less toxicity was reported in the MPA arm. Conclusion: A single MPA dose seems to be well tolerated and more effectively reduces hot flashes than does venlafaxine.