Background Melasma continues to be a disease that is difficult to treat with no fully satisfactory results. The role of a fractional CO2 laser in its treatment is controversial. The addition of tranexamic acid (TXA) might be helpful. Objectives To assess the efficacy of a low‐power fractional CO2 laser alone versus its combination with tranexamic acid used either topically or intradermally for melasma treatment. Methods A randomized comparative split‐face study included a total of thirty female patients with bilateral, symmetrical melasma. The whole face was subjected to treatment via a low‐power (12 Watts) fractional ablative CO2 laser. One side was randomly assigned to topical application of tranexamic acid solution after the session immediately or intradermal microinjection of tranexamic acid prior to the laser session. Sessions were conducted every 4–6 weeks for five consecutive sessions. Assessments were done using the melasma area severity index MASI score, melanin index (MI), and erythema index (EI) before sessions and 2 weeks after the final session. Results After treatment, there was significant reduction in the MASI score on both sides of the face; the side treated with the fractional CO2 laser alone and the side treated with fractional CO2 laser combined with TXA (topically or intradermal injection) (P‐values 0.007, <0.001, and 0.016, respectively). MI was significantly lower on the side receiving fractional CO2 laser alone and the side receiving fractional CO2 laser combined with intradermal injection of TXA (P‐values <0.001 and 0.003, respectively), while the EI showed significant improvement only on the side receiving fractional CO2 laser alone (P‐value = 0.023). Although patients reported no differences in improvement on either treated side, the degree of improvement regarding the MASI score was better on the side receiving fractional CO2 laser alone. Regarding MI, the degree of improvement was higher on the side receiving fractional CO2 laser combined with intradermal injection of TXA than on the side receiving fractional CO2 laser alone; however, this improvement did not reach statistical significance. Minimal complications occurred in the form of mild pain. Conclusion A low‐power fractional CO2 laser is an effective, safe treatment for melasma. However, the addition of tranexamic acid (either topically or intradermally) to a fractional CO2 laser should be further studied. Lasers Surg. Med. 51:27–33, 2019. © 2018 Wiley Periodicals, Inc.