This study examined whether the prostaglandin E(1) analogue misoprostol (400 microgram), when placed vaginally at the time of intrauterine insemination (IUI) improves pregnancy rates. A prospective, placebo-controlled, randomized and double-blind study involving 274 women in 494 IUI cycles resulted in a total of 64 pregnancies (13% per cycle). Misoprostol cycles totalled 253, with 43 pregnancies (17% per cycle), whereas placebo cycles totalled 241, with 21 pregnancies (9% per cycle). The cumulative pregnancy rate with misoprostol treatment was significantly greater than with placebo (P = 0.004, Cox proportional hazards regression). The benefit of misoprostol was seen in clomiphene cycles (14 versus 4%, P = 0.006), and was indicated in FSH cycles (33 versus 15%, borderline significance) and natural cycles (15.6 versus 7.7%, not significant), but was not seen in clomiphene/FSH cycles (18.2 versus 23.5%, not significant). Misoprostol treatment did not increase pain score on the day of IUI (1.1 versus 1.4) and at 1 day post IUI (0.6 versus 0.8). Complications were rare in both groups [six (2%) subject cycles in the misoprostol cycles compared with two (1%) in the placebo group]. It is concluded that the use of vaginal misoprostol may improve the chance for pregnancy in women having IUI in a wide variety of cycle types.