Isobutylamido thiazolyl resorcinol (ITR) is a novel anti-tyrosinase recently shown to be effective in the treatment of hyperpigmentation. Low-fluence Q-switched Nd:YAG 1064-nm laser (LFQS) has proven to be effective for various hyperpigmentary conditions. However, there is no study on the efficacy and safety of combined ITR and LFQS treatment. To compare the efficacy and safety of combined ITR and LFQS with LFQS monotherapy for facial hyperpigmentation. Patients with symmetrical facial hyperpigmentation were treated with five sessions of once weekly LFQS on the whole face. One side was randomly treated with ITR and the other side received a placebo cream for 12weeks. Patients were followed for 8weeks after the last laser treatment. Relative lightness index (RL*I), Facial Hyperpigmentation Severity Score on the malar area (FHSSm ), patient satisfaction, recurrence, and adverse events were recorded. Twenty-four patients completed the study. Both sides demonstrated significant reductions of mean RL*I and mean FHSSm from baseline (P<.01). At the 4th week, the ITR-treated side showed more improvement of mean RL*I than the placebo-treated side (62.5% vs 47.3% improvement, P<.05). The mean FHSSm on the ITR-treated was reduced at a significantly higher percentage than the placebo-treated side (54.4% vs 40.2% reduction, P<.05). Partial recurrence was observed on both sides. No serious side effects were noted. Combined ITR and LFQS therapy was more superior than LFQS monotherapy in the treatment of facial hyperpigmentation. ITR may serve as adjuvant for patients with such condition.