Glutathione is a well-known potent antioxidant which also possesses skin-lightening and anti-aging properties. Despite its popularity as main ingredients on skin care and supplementation, the anti-aging effect of of oral and topical glutathione combination is unknown. This study aimed to compare the anti-aging effect of oral and topical glutathione combination therapy against monotherapy and placebo. A randomized, double-blind, placebo-controlled clinical trial was conducted on healthy women aged 25-50 years old. The subjects were randomly assigned into one of four intervention groups (I=topical glutathione + oral placebo; II=topical + oral placebo; III=topical + oral glutathione; IV=topical placebo + oral glutathione). The clinical changes on spots, pores, roughness, wrinkles, signs of ultraviolet acnes (UV-A), and ultraviolet spots (UV-S) were assessed biweekly with Janus-II measurement system for a total of 8 weeks. Mann Whitney U test was used to compare the mean difference between each glutathione group (I, III, IV) and placebo group (II). Group IV demonstrated the least increase of spots and significant reduction of pores and roughness compared to placebo (p<0,05). Group I experienced the most reduction in wrinkles and UV spot parameter (p<0,05). Whereas group III shows the biggest improvement on UV acne parameter (p<0,05). The study shows the benefits of topical and/or oral glutathione on defying the skin aging process compared to the placebo. However, the combination of oral and topical glutathione is not as effective as monotherapy, except in UV acne parameter.