Background: The purpose of this study was to compare the effectiveness of Letrozole versus Clomiphene citrate for ovulation induction in polycystic ovarian syndrome (PCOS) with infertility. Methods: This was a prospective randomized trial involving 150 women with PCOS attending the Infertility Clinic at three hospitals in Malaysia. During the initial visit, anthropometric measurements and baseline investigations were performed. Patients were randomized to 5.0 mg Letrozole daily (75 patients) or 100 mg Clomiphene citrate daily (75 patients) from the fifth until the ninth day of menstruation. Serial transvaginal scans were performed to see the dominant follicles, endometrial thickness and number of follicles. Transvaginal scans were performed serially to look for evidence of ovulation. Results: The subjects were homogenously distributed. The difference between Letrozole and Clomiphene citrate for ovulation rate was 59 (78.7%) versus 40 (53.3%). Patients taking Letrozole exhibited a mean endometrial thickness (ET) at mid cycle of menses (Day 11-D14) of9.2 mm(SD ± 2.3) versus8.4 mm(SD ± 2.2) for patients taking Clomiphene citrate, and these differences were statistically significant (p < 0.001). In terms of pregnancy rate, Letrozole facilitated pregnancy induction in 19 patients (25.3%) versus 12 patients (16.0%) for Clomiphene citrate; however, this was not statistically significant (p = 0.22). More dominant follicles exhibiting a monofollicular morphology were observed in patients treated with Letrozole compared to patients treated with Clomiphene citrate, with a monofollicular dominant follicle observed in 33 (46.5%) versus 20 (26.7%) patients, respectively. Conclusion: Letrozole provided a more efficient stimulation compared to Clomiphene citrate in terms of ovulation induction, thickening of the endometrial lining and achievement of a successful pregnancy. Clinical Trials. gov Identifier: NCT015-77017.