The safety and efficacy of a novel skin-lightening cream (SLC) with 4% hydroquinone (HQ), which additionally contains 4 skin-brightening actives, was compared with a triple combination cream (TCC) with 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide for the treatment of melasma under measures of sun protection. The study was a randomized, investigator-blinded, split-face study including 20 Caucasian females with at least mild epidermal or mixed melasma. Evaluations were made before treatment, after 4 and 8 weeks, and after 12 weeks at the end of the once-daily treatment period with the creams. The evaluations included the investigator's tolerability assessments, the Investigator's Global Assessment, the Melasma Area and Severity Index (MASI), and a participant questionnaire. Under the conditions of the present study, the SLC was comparable in both efficacy and tolerability with the well-established TCC treatment for facial melasma. The MASI reduction became significant for both creams after 4 weeks and reached -77% for SLC and -79% for TCC cream after 12 weeks of once-daily use under measures of sun protection. None of the subjects discontinued treatment because of an intolerability or adverse event. About one-third of the subjects experienced at least one local intolerability (eg, erythema, dryness, or peeling) with both creams over the entire study period, while the remaining subjects did not experience any intolerabilities.