BackgroundMelasma is a chronic dermatosis that impacts the patient's quality of life and can present considerable challenges in terms of effective treatment.ObjectiveTo evaluate the effectiveness, tolerability, and safety of 5% cysteamine combined with 4% nicotinamide in female subjects with melasma.MethodsThis single‐center, single‐arm, prospective, open‐label study evaluated patients with melasma using a combination cream of 5% cysteamine and 4% nicotinamide in a progressive regimen (60 min in the first month, 120 min in the second month, and 180 min in the third month).ResultsOverall, 35 treated subjects exhibited reduced modified Melasma Area and Severity Index (mMASI) (p < 0.001) and decreased MelasQoL scores (p < 0.001), accompanied by improved brightness, luminosity, homogeneity, and spot intensity (p < 0.001). Photographic and colorimetric analysis revealed smaller spots and improved homogeneity.LimitationsAdherence to progressive daily treatment could not be evaluated long‐term.ConclusionA combination cream comprising 5% cysteamine and 4% nicotinamide was effective, tolerable, and safe for treating melasma.