AIM: To compare vaginally administered misoprostol to rectally administered misoprostol and placebo in a prospective randomized placebo-controlled study. METHODS: One hundred and fifty women with singleton vaginal deliveries were randomized (50 women in each arm) to receive 400-microg misoprostol tablets (crushed and suspended in a microenema) intravaginally, or 400-microg misoprostol tablets rectally, or two placebo lactose tablets rectally. The medication was administered immediately after delivery of the placenta. Women with profuse hemorrhage and delayed placental separation (>30 min) were excluded. Our outcome measures were postpartum blood loss 1 h after administration, and change in hemoglobin and hematocrit values from baseline to postpartum day 1. Analysis of variance and chi-squared tests were used to compare the outcome variables between groups. RESULTS: One hundred and twenty-six women were available for analysis. Baseline characteristics were similar across the groups. The number of excluded subjects, the estimated blood loss, and the drop in hemoglobin and hematocrit values did not differ between the three groups (P > 0.05). CONCLUSIONS: Misoprostol administered vaginally or rectally at a dosage of 400 microg following placental separation was not effective for decreasing postpartum bleeding in women without excessive hemorrhage.