Background: In Developing world, Olanzapine at a dose of 10mg is associated with excessive somnolence. Recently, reduced dose Olanzapine 5mg has been found to be equally effective with less sedation. Hence, we intended to conduct a study comparing the efficacy, safety, and cost effectiveness of reduced dose Olanzapine 5mg vs Aprepitant. Objectives: To compare Complete response (no emesis and no rescue therapy) rates between the two groups during three periods: 0 to 24 hours (acute), 25 to 120 hours (delayed), and 0 to 120 hours (overall) after chemotherapy. To compare nausea control rates in the acute, delayed, and overall periods. To evaluate potential adverse effects and compare cost effectiveness of Olanzapine, Aprepitant. Methods: All newly diagnosed cancer patients who were scheduled to receive highly emetogenic chemotherapy (either cisplatin at a dose ≥70 mg/ m2 body surface area, with or without other chemotherapeutic agents, or doxorubicin at a dose of 60 mg/m2 plus cyclophosphamide at a dose of 600 mg /m2) and had a European Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 were randomized 1:1 to receive triple anti emetic regimen comprising of 5HT3 antagonist (Palonosetron)+Steroid (Dexamethasone) + either NK1 antagonist (either Aprepitant 125mg on day 1, 80 mg on days 2, 3 or Fosapprepitant 150mg IV on day 1) or Olanzapine 5mg once daily on days 1-4). Number of Vomiting episodes, use of rescue therapy, nausea, other adverse effects were recorded. Results: A total of 154 patients were eligible for the study, 77 in each arm. The Complete response rates for Aprepitant and Olanzapine during the acute period were 79.22% and 81.81% respectively (p > 0.05), during the delayed period were 74.02% and 70.12% respectively (p > 0.05), during the overall period were 74.02% and 70.12% respectively (p > 0.05). Nausea control rates for Aprepitant and Olanzapine during the acute period were 74.42% and 84.82% respectively (p > 0.05), during the delayed period were 45.45% and 68.83% respectively (p < 0.05), during the overall period were 45.45% and 68.83% respectively (p < 0.05). Most common side effect in patients receiving Olanzapine was Somnolence which was observed in 12.98% patients (CTCAE Grade 2). Most common side effect in patients receiving Aprepitant was fatigue which was seen in 6.5% patients. A 4-day course of Olanzapine costs INR-20/- while a 3-day course of Aprepitant costs INR-1000/- and a single 150mg IV Fosapprepitant costs INR 2500/-. Conclusions: In the developing world, Olanzapine 5mg can be considered as an effective, safe, and a cheaper alternate to Aprepitant as a component of triple antiemetic regimen in the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy.