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BACKGROUND Melasma is a challenging pigmentation disorder. OBJECTIVE To assess and compare the efficacy of tranexamic acid (TXA) intradermal microinjection alone versus its combination with low-power, low-density fractional CO2 laser in a sequential pattern in melasma. Patients and Methods This study included 29 patients with melasma. Half of the face was randomly assigned to fractional CO2 laser; the other half to TXA. This split-face session was repeated every 6 weeks for 3 sessions. In between, TXA was applied to the full face every 2 weeks. Treatment duration was 4 months. Dermoscopy, melanin index (M.I), and erythema index (E.I) were evaluated at baseline and 4 weeks after the last session. RESULTS Melanin index, E.I, total dermoscopic score and different dermoscopic patterns of pigmentation, and vascular features showed significant reduction posttreatment on both sides of the face. No statistically significant difference was found regarding the degree and percentage of improvement in M.I, E.I, and total dermoscopic score between both sides. CONCLUSION Tranexamic acid microinjection alone or combined with low-power, low-density fractional CO2 laser in a sequential pattern are comparatively effective and safe for melasma treatment; however, combined treatment is recommended. Dermoscopy is an essential noninvasive tool in the assessment of melasma and monitoring patients' response to treatment.