Background: Intra-myometrial injection of vasopressin during myomectomy is another method that could minimize of blood loss during myomectomy. However, there is paucity of knowledge to guide its use in myomectomy. Objective: To assess the efficacy of intra-myometrial vasopressin by determining whether it is noninferior to (as good as) a placebo in reducing intra-operative blood loss during abdominal myomectomy. Methods: This was a randomized, double-blind non-inferiority trial. This study was carried out in University of Abuja Teaching Hospital from September 2016 to May 2017. One hundred and twenty-eight patients with uterine leiomyoma of 14 – 30 weeks size they were randomized to either receive 20 IU (1 ml) of vasopressin in 19 mls of normal saline or 20 ml of normal saline at the planned uterine incision site during myomectomy after traditional tourniquet application. Myomectomy was then performed and the efficacy of vasopressin was assessed by a primary outcome and two secondary outcomes. P-value < 0.05 was considered statistically significant at 95% confident level. Results: A total of 128 women were randomized. However, only data from 125 women were analyzed. The mean estimated blood loss in the vasopressin group was 503.2 ml (SD, 97.5) compared with 841.3 ml (SD, 316.0) In the placebo group. The adjusted mean difference in intraoperative blood loss between the two groups, -359.3 (95% CI = -426.2 to -292.4), was statistically significant (p < 0.001). Post-operatively, the mean packed cell volume was significantly higher in the vasopressin group compared with the placebo group (29.5%, SD = 1.6 versus 27.7%, SD = 2.0; p<0.001). Furthermore, the need for blood transfusion was significantly higher in the placebo group compared with the vasopressin arm (OR =5.06; 95% CI = 2.07 – 12.4; p<0.001). Uterine size was a significant independent predictor of estimated blood loss in both groups (p < 0.001). Conclusion: Intra-myometrial vasopressin injection significantly reduced blood loss during abdominal myomectomy in this study.