Background: The polycystic ovarian syndrome is a common cause of anovulation leading to female infertility. Treatment given classically was Clomiphene citrate. New therapy available is Letrozole, a third-generation aromatase inhibitor. It is more effective in induction of ovulation in PCOS compared to Clomiphene citrate & has minimal side effect, no teratogenicity & is cost-effective. Objective: To assess the effectiveness of letrozole in comparison to Clomiphene citrate as the initial therapeutic approach for stimulating ovulation in women diagnosed with Polycystic Ovary Syndrome (PCOs). Material and Methods: This experiment, which was both randomized and controlled, occurred from January 2017 to June 2017 at Unit III of the Department of Obstetrics & Gynaecology, Sheikh Zaid Women Hospital in Larkana. A total of 100 participants (50 in each category A & B), aged between 20 and 38 years, experiencing polycystic ovary syndrome (PCO) with anovulatory infertility were chosen. Individuals with uterine and adnexal abnormalities, ovarian cysts, hyperprolactinemia, and prior surgeries related to the genital tract were excluded. Category A received treatment with Clomiphene citrate, while category B received Letrozole. Results: The average age with standard deviation (SD) in group-A was 28.28 ± 5.91 years, whereas in group-B, the mean age ± SD was 29.06 ± 4.94 years. The age range was 20-38 years. In terms of body mass index (BMI), the mean ± SD for group-A was 30.10 ± 4.45, and for group-B, it was 31.27 ± 4.69 Kg/m2. Letrozole demonstrated greater efficacy, with a pregnancy rate of 22%, compared to only 08% with Clomiphene citrate. The effectiveness of both drugs was influenced by the age and BMI of the patients. In younger and overweight women, the efficacy of both drugs was lower (P values = 0.219 & 0.560). Conclusion: Letrozole exhibits a greater success rate than Clomiphene when addressing infertility in individuals with polycystic ovarian syndrome. It is advised to employ Letrozole specifically for this objective.