Background: Isotretinoin is the most potent anti-acne agent available today and only one that addresses all pathogenic mechanism; However, it is associated with multiple dose-dependent side effects. Objective: To evaluate the efficacy and tolerability of various therapeutic regimens (daily; alternate and low dose) of oral isotretinoin in moderate to severe acne vulgaris. Methods: This randomised, prospective, single-blind, parallel-group study was carried out in 90 randomised with a group of 30 patients each categorized as Group A receiving a conventional daily dose of oral isotretinoin 0.5mg/kg/day for 24 weeks, Group B receiving alternate day dose of oral isotretinoin 0.5mg/kg for 24 weeks and Group C receiving low dose 20 mg daily regimen of oral isotretinoin for 24 weeks for the total duration of 24 weeks with every 2 weeks follow up visits for their efficacy and safety. Results: Out of total 90, only 6 patients lost to follow up during study period, so remaining 84 patients included in the final analysis as 27 patients in Group A, 28 patients in Group B and 29 patients in Group C. The comparison of mean initial acne load at each visit in all three groups suggested no significant difference at initial acne scores in various treatment groups, which was found to be significantly decreased at each follow-up and the end of therapy and no significant difference at the end of the therapy. Frequency of all the side effects was higher in treatment group A. Severity of the all the side effects including mucocutaneous and systemic were maximum in group A and minimum in group C. Conclusion: Looking at the efficacy and safety profile of various oral isotretinoin regimens, one can plan for reducing dose regimen of oral isotretinoin for severe acne and low dose isotretinoin for mild to moderate acne.