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Objectives: Melasma is a common melanin disorder in vietnamese women. Various approaches still show limitations. Polynucleotide, known as bio-regenerative injection could play the role in hypopigmenting properties. Introduction: To compare the efficacy and safety of combination with oral tranexamic acid, topical cysteamin 7.5% and polynucleotide (PN) injection in the treatment of melasma Materials / method: 60 female patients of facial melasma were divided in to 3 groups. Group A (20 patients) was only injected 20mg polynucleotide (PN) for 3 times every 2 months. Group B (20 patients) were described oral 500mg tranexamic acid per day, applied cysteamin 7.5% cream every day. Group C (20 patients) was asked to take the same oral pills, skincare routine and injected PN solution for 3 times within 6 months. We recorded digital potograghs, modified melasma area severity index (mMASI), redness, patients satisfaction and downtime for evaluating. Results: All groups showed significant changes in modified melasma area and severity index (mMASI) score after using the treatment (P<0.05). However, group C showed the highest improvement (>75%) in mMASI as compared to group B (60%) and group A (30%) after 6 months. There was 4 patients (20%) in group B complained abour irritation due to topical cysteamin 7.5% meanwhile there was no report in group C. There is down time from 24-48h in injected group and lowest satisfaction in group A Conclusion: Oral TXA, topical cysteamin 7.5% was effective in melasma treatment. However, the decreasing of irritation rate and increasing of brightening effect was mentioned with polynucleotide injection.