Introduction: Emerging studies have also shown that patients with acne are under increased cutaneous and systemic oxidative stress. The current studies indicate that Isotretinoin treatment induces oxidative stress and liver damage but Azithromycin posses internal antioxidant property.Aim and objectives: The aim of the study is to determine the oxidative stress in acne vulgaris by measuring the levels of an oxidant [malondialdehyde (MDA)] and an antioxidant [superoxide dismutase (SOD) enzyme] in acne patients taking therapy with Isotretinoin, Azithromycin and its combination. Materials and Methods: Total of 125 patients with mild to moderate grade of acne of both sexes aged between 14–35 years were divided in five different groups– control group, patients of  acne not taking any treatment, on isotretinoin therapy, on azitrhomycin therapy and taking combination therapy. MDA levels and SOD levels are compared within and among the groups. Results: In our study, the MDA level was significantly increased in group of Acne patients not taking any treatment whereas very high significant increase in MDA level were noted in group of Acne patients on Isotretinoin therapy. Group of patients taking Azithromycin and combination therapy also showed significant rise in MDA level but less marked than group of acne patients and group of patients taking Azithromycin therapy. It was found that increase in SOD level was very highly significant in group of Acne patients not taking any treatment and significant increase in group of Acne patients on Azithromycin therapy whereas patients in Group taking Isotretinoin and a combination therapy show comparatively less but significant rise in SOD levels. Conclusion: Oxidative stress exists in acne which may exacerbate due to Isotretinoin monotherapy but may get balanced with its combination with macrolides. The macrolides like Azithromycin possess antioxidant property. Combined therapy of Isotretinoin and Azithromycin will be more effective with less stress than the either drug alone.Our small data is useful to plan the acne therapy. This information is helpful to select antiacne agents that have different mechanisms of action to give synergistic effects. Until new drug therapies are developed, it will be useful to prefer at least one antioxidant–featured drug along with the Isotretinoin in management of acne.