Background: Melasma has a complex pathogenesis, and various aggravating factors contribute to its recalcitrance to treatments. A combination of isobutylamido thiazolyl resorcinol (ITR) and hyaluronic acid (HA) could increase melasma treatment efficacy.

Aims: To compare the efficacy and safety of 0.15% ITR plus HA vs 0.15% ITR or HA alone in melasma treatment.

Methods: Ninety-two patients received ITR 0.15% plus HA (n = 30), 0.15% ITR (n = 31), or HA (n = 31) along with broad-spectrum sunscreen application for 12 weeks. Treatment efficacy was determined using modified Melasma Area Severity Index (mMASI), average melanin and melanin variation with Antera3D^® , and safety based on transepidermal water loss.

Results: Compared with the HA group, the ITR+HA group showed significantly reduced mMASI at weeks 4, 8, and 12 (p = 0.026, 0.015, and 0.001, respectively), whereas the ITR group showed a significant reduction at week 12 (p = 0.027). There was no significant difference in the mMASI or average melanin level between the ITR+HA and ITR groups. Melanin variation was significantly lower in the ITR+HA group than in the ITR group at weeks 4, 8, and 12 (p = 0.027, 0.019, and 0.023, respectively).

Conclusions: The combination of 0.15% ITR and 0.15% ITR+HA effectively reduced melasma severity. HA could synergistically improve melasma homogeneity.