Treatment of melasma, a hyperpigmentation disorder, remains a challenge. The primary objective of two 8-week, multicenter, randomized, investigator-blind studies was to compare the efficacy and safety of a hydrophilic cream formulation containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination agents tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All agents had the same drug concentration and vehicle. A total of 641 adult patients, predominantly female, with moderate to severe melasma and Fitzpatrick skin types I through IV, were randomized to the various treatment groups. Due to the similarity of the study designs, the results of the 2 studies were combined and are reported here. The primary efficacy analysis involved the proportion of intent-to-treat patients in each treatment group whose condition had completely cleared by week 8. The results of the combined clinical trials demonstrated that significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with the other treatment groups (4.6%) at the end of week 8 (P<.0001). In addition, at week 8, a 75% reduction in melasma/pigmentation was observed in more than 70% of patients treated with RA+HQ+FA compared with 30% in patients treated with the dual-combination agents. The most common adverse reactions seen with all treatment groups were erythema, skin peeling, burning, and/or stinging sensation. The majority of treatment-related adverse events were of mild severity.