Melasma is an acquired pigmentary disorder that most commonly occurs in women of child-bearing age. Melasma is therapeutically challenging, and most commercially available hypopigmenting agents include tyrosinase inhibitors, which regulate the rate-limiting step of melanogenesis. 4-n-Butylresorcinol has received considerable attention as a novel hypopigmenting agent in the last 15 years because it has an inhibitory effect against tyrosinase and tyrosinase-related protein-1. However, the hypopigmenting effect of 4-n-butylresorcinol in human subjects has only been shown in a few studies. Liposome encapsulation is known to improve stabilization and enhance penetration of the product. Therefore, this study was conducted to evaluate the hypopigmenting efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream in patients with melasma. This was a randomized, double-blind, vehicle-controlled and split-face comparison study. Twenty-three patients with a clinical diagnosis of melasma were included. 4-n-Butylresorcinol 0.1% cream or vehicle was applied to each side of the face twice daily for 8 weeks. Clinical and photographic evaluations, Mexameter measurements and assessment of patient satisfaction and side-effects were performed at baseline, 4 and 8 weeks. All subjects completed the study. Mexameter measurements demonstrated that the melanin index of the 4-n-butylresorcinol-treated side showed a significant decrease when compared with the vehicle-treated side after 8 weeks (P = 0.043). No adverse reactions were observed throughout the study. Subjectively, 4-n-butylresorcinol was considered to be efficacious in more than 60% of the patients after 8 weeks of treatment. In conclusion, liposome-encapsulated 4-n-butylresorcinol 0.1% cream was well tolerated and showed significant higher efficacy than vehicle alone for the treatment of melasma.