The aim of this study was to compare the efficacy and safety of a triple combination (TC) cream and monotherapy with hydroquinone (HQ) cream in the treatment of moderate to severe facial melasma. A total of 120 patients applied TC cream once daily or HQ cream twice daily for 8 weeks. Evaluations included static global severity assessment of melasma, improvement of melasma over time, local tolerability, and adverse events. TC cream was significantly more effective than HQ cream from week 4 onwards: lesions were approximately equivalent to the surrounding skin in 35% of all TC-treated patients, compared to 5% of those who used HQ cream (P = 0.0001). Improvement of more than 75% was achieved by 73% of TC cream patients and 49% of HQ cream patients (P = 0.007). The incidence of adverse events (erythema, burning sensation, and desquamation) was similar in both groups. No patient dropped out of the study because of drug-related adverse events. TC cream was more effective than the HQ cream for the treatment of moderate to severe facial melasma. Both products had similar safety profiles.