Background: Treatment of melasma remains a challenge and involves multistep approach. Diacetyl boldine (DAB) stabilizes tyrosinase in its inactive form while TGF‐β1 biomimetic oligopeptide‐68 inhibits tyrosinase activity.

Aims: (1) to study the efficacy and safety of the combination use of two formulae containing two principal ingredients: DAB and TGF‐β1 biomimetic oligopeptide‐68 on facial melasma, and (2) to compare their efficacy with 2% and 4% hydroquinone cream (HQ) on sun‐protected normal skin.

Methods: A randomized, double‐blind, 12‐week comparative study of pre‐/post‐treatment was conducted in 40 females. Melasma was evaluated by manual MASI score and MASI score with instrumentally graded darkness at baseline, 6th week, and 12th week. The author also compared their effect with HQ on the arms, assessed their safety profile throughout the study.

Results: Thirty‐eight subjects have completed the study. Their melasma showed improvement at the 6th week and 12th week as compared with baseline (P < 0.05). None developed severe reaction. Most subjects had temporary, mild skin reaction. About 2.6% of subjects graded themselves markedly improved, 76.3% moderately improved, and 21.1% slightly improved. Each formula showed either more efficacy or exerted faster action on pigment reduction than HQ.

Conclusion: Combination of DAB serum at night and DAB/TGF‐β1 biomimetic oligopeptide‐68/sunscreen cream in the morning and at noon was effective and safe for facial melasma. They were superior to HQ in pigment reduction.