Purpose <p>Melasma is a chronic, acquired disorder of focal hypermelanosis. It clinically presents as hyperpigmented patches over photo-exposed areas such as the face. The study aimed to evaluate the efficacy and safety of combined fractional CO2 laser with topical tranexamic acid (TA) versus combined fractional CO2 laser with topical ascorbic acid in treating patients with melasma.</p> Methods <p>Forty individuals, spanning the ages of 20 to 50, diagnosed with melasma were included in this prospective split-face comparison study. Patients were subjected to detailed medical, skin, dermoscopic, and Woods light, digital skin assessment for their grading of melasma before and after treatment. Subjects received fractional CO2 laser sessions to the affected areas before applying 10% solution of TA on the right side and 20% ascorbic acid solution on the left side.</p> Results <p>Baseline dermoscopic examination of the right side showed that 62.5% of the patients had fading of pseudo reticular network, 22.5% had fading telangiectasia, while the other 15% had no change. Considering the left side, 55% had fading of pseudo reticular network, 40% had fading telangiectasia, while the other 5% had no change. The baseline characteristics of melasma were comparable except for vascularity which was significantly higher in the right side compared to the left (<i>p</i> = 0.007).</p> Conclusion <p>Trans-epidermal delivery of tranexamic acid or vitamin C after low power fractional CO2 laser is a useful tool with more superiority towards the tranexamic acid treatment. More controlled larger sample trials are required to establish an optimal and effective treatment for melasma.</p> Graphical abstract <p></p>