Objective To assess the effect on intra-operative blood loss of using pre-operative sublingual misoprostol in abdominal and laparoscopic myomectomy surgeries compared to placebo. Design Double-blind placebo-controlled randomised study. Setting A single tertiary Gynaecology Unit in Melbourne, Australia. Population Women 18 years old undergoing laparoscopic or open myomectomy surgery. Methods Fifty three women undergoing laparoscopic or abdominal myomectomy surgery for symptomatic uterine leiomyomas were randomised to pre-operative sublingual 400mcg misoprostol (n=26) or placebo (n=27). Main Outcome Measures The primary outcome measure was intra-operative blood loss. Results There was no significant difference in intra-operative blood loss at myomectomy surgery between the misoprostol and placebo groups. Intraoperative blood loss in the misoprostol treatment group was 306ml +/- 281ml, compared to 325  352 ml in the placebo group; P=0.83. Both groups were adequately matched for baseline demographics and myoma size. Conclusions The study was not able to demonstrate that pre-operative sublingual misoprostol use at laparoscopic and abdominal myomectomy surgery resulted in a statistically significant reduction in intra-operative blood loss. This study provides a foundation for adequately powered trials assessing the effect of sublingual misoprostol on blood loss at myomectomy. Funding Funding was supplied via an Australia Gynaecological Endoscopy and Surgery Society (AGES) Research Grant. There were no conflicts of interest in this trial. Keywords Leiomyoma, myomectomy, misoprostol, blood loss, sublingual Tweetable abstract Pre-operative sublingual misoprostol may reduce intra-operative blood loss during myomectomy surgery but confirmation is required from a larger study.