To evaluate the effectiveness of 1% cysteamine, 3% Tranexamic Acid, 4% Niacinamide and 2% Galactomyces ferment filtrate serum in treating epidermal melasma patients. The design study of this paper is a pretest-posttest clinical trial. The 1% cysteamine, 3% Tranexamic Acid, 4% Niacinamide and 2% Galactomyces Ferment Filtrate serum was applied on both malar area and left overnight. Melasma on the frontal area was left untreated. Five follow-up sessions were performed on a biweekly basis, with parameters for hyperpigmentation measured using Chromameter, Mexameter and mMASI score. Data acquired were processed using paired T-Test, one-way Anova and Wilcoxon in SPSS 27. The study was conducted at Hasanuddin University Hospital and Wahidin Sudirohusodo, Makassar, South Sulawesi Indonesia from April-June 2021. Participants: 27 female patients with epidermal melasma on the malar and frontal region. A total of 27 female patients with epidermal melasma on the malar and frontal regions who met the inclusion criteria underwent a 7-week study between April-June 2021. A statistically significant increase in L* value was found between week-0 (W0) and W7 (p=.000), with improvement from W5 (p=0.005) to W7 being the most significant (p=0.000). Melanin index decreased after treatment but was statistically not significant (p=>0.05), as well as erythema index. There was a 54% decrease in mMASI score on treated areas between W0 and W7 (P=0.000). Approximately 11% of subjects (3/27) experienced pruritus and burning sensation during initial therapy. The combination serum showed promising depigmentation effect on epidermal melasma patients with minimal side-effects.