Atypical antipsychotics have become the mainstay of therapy for psychosis. Though extrapyramidal side effects have been reduced with atypical antipsychotics, yet there are increased concerns over metabolic effects. The present study is aimed to comparatively evaluate the metabolic profile of olanzapine and iloperidone in cases of psychosis. A prospective, randomized, open label, observational study of 6 months duration was conducted in the Department of Pharmacology and Department of Psychiatry, Rohilkhand Medical College and Hospital, Bareilly. A total of 62 patients of both sexes newly diagnosed with psychosis (ICD-10, F20- F29) were included in the study, 31 each in olanzapine and iloperidone groups. Demographic parameters were recorded, following which the patient’s body weight, BMI, fasting blood sugar and lipid profile were estimated at baseline. Follow-up of the patients was done periodically after one month, three months and six months. Olanzapine treated patients showed markedly significant rise in body weight up to 7 kg at the endpoint (p<0.0001) at each follow-up, with a significant increase in BMI. Rise in fasting blood sugar (FBS), total cholesterol (TC), triglycerides (TG) and low-density lipoprotein (LDL) levels werealso statistically significant. At the same time, significant decrease in HDL levels was also observed. Iloperidone treated patients showed statistically significant less rise in body weight (upto 1kg, p<0.05) and BMI. No significant changes in fasting blood sugar, total cholesterol, LDL and HDL levels were noted, while TG levels were significantly reduced. Iloperidone caused numerically less rise in bodyweight and BMI, and fewer metabolic adverse effects as compared to olanzapine, and hence should be preferred. Keywords: Atypical antipsychotics; Weight gain; Blood sugar level; Dyslipidemia