Objective: To evaluate the efficacy and safety of vaginal misoprostol for cervical priming before diagnostic outpatient hysteroscopy (OH) without anesthesia. Design: Double-blind randomized controlled trial. Setting: University teaching hospital. Patient(s): One hundred fifty patients requiring diagnostic OH for investigation of infertility or abnormal uterine bleeding in the reproductive age. Intervention(s): Patients were randomly allocated into two equal groups (n = 75). In group I, 200 mu g misoprostol was inserted into the posterior vaginal fornix 3 hours before OH; in group II (control), vaginal examination was performed without misoprostol administration. A rigid 30 degrees 4-mm hysteroscope was used in the vaginoscopic technique. Main Outcome Measure(s): Ease of cervical entry (Likert scale), procedural time, patient acceptability (Likert scale), and pain scoring (visual analog scale). Result(s): Vaginal misoprostol significantly facilitated the procedure; cervical entry was easier, procedural time was shorter, patient acceptability was higher, and pain scoring was lower in group I compared with group II. Side effects of misoprostol were infrequent, minor, and transient. No complications were reported. Conclusion(s): The regimen of 200 mg vaginal misoprostol administered 3 hours before diagnostic OH is a simple, effective, and safe method of cervical priming to facilitate the procedure without anesthesia. (Fertil Steril (R) 2011; 96: 962-5. (C)2011 by American Society for Reproductive Medicine.)