Background: Melasma is an acquired increased pigmentation of the skin characterized by symmetrical and confluent grey-brown patches usually on the areas of the face exposed to the sun. Silymarin strongly prevents photocarcinogenesis, and significantly prevented melanin production. The objectives of this study were the assessment of safety and efficacy of topical Silymain (SM) cream in a double-blind placebo controlled study for treatment of melasma patients., Methods: Experimentally on 24 Albino rabbits were randomly divided into 4 equal groups. [A] No treatment, [B] received placebo, [C] treated with SM cream (0.1), & [D] treated by SM (0.2), were applied topically before UV sun light exposure for 30 days, assessed clinically & tissue pathology. Clinically on 96 adults diagnosed with melasma randomized to three equal groups to receive one of the tested drugs applied twice daily for 4 weeks, evaluated by the response; lesion size, melasma area and severity index score, Physician global assessment, and subjective assessment., Results: The Clinical and histopathology observations were reduced significantly in SM groups. Clinically; all patients showed significant excellent pigment improvement & lesion size reduction with SM treatments from the 1st week. All patients were fully satisfied 100%. No side effects were observed., Conclusions: Silymarin showed tremendous improvement of melasma in a dose-dependent manner, and was effective in prevention of skin damage caused by U.V. sunlight. It is a safe new candidate effective treatment for melasma., Trial Registration: Australian New Zealand Clinical Trials Registry - ACTRN12612000602820.