New topical treatments for acne vulgaris are needed for patients who are intolerant of current treatments. Salicylic acid (SA) is an over-the-counter antiacne treatment, and tretinoin is a commonly used prescription antiacne cream. The authors sought to compare efficacy and tolerance of a formula containing SA and a lipophilic derivative of SA (lipohydroxy acid [LHA]) versus a tretinoin cream in participants with mild acne vulgaris. Primarily, the authors wanted to establish equivalent efficacy between these 2 creams. The authors conducted a randomized, double-blind, prospective trial enrolling 85 participants with mild to moderate facial acne. All participants had less than 10 inflammatory lesions and 20 to 40 comedones. Participants were randomized to receive either cream containing SA plus LHA twice a day or tretinoin once daily for 87 days. Efficacy and tolerability were assessed by both the participants and the investigator at days 0, 28, 56, and 87. At the conclusion of the study, participants also completed a questionnaire with regards to efficacy and the cosmetic properties of their given cream. Seventy-three participants completed the study, of which 37 used SA/LHA and 36 used tretinoin. With the exception of pustules (P=.10), all lesion types (open comedones, closed comedones, and papules) decreased significantly with both creams from day 0 to day 87 (P<.0001, P<.0001, P=.0001, respectively). This decrease did not significantly vary between the 2 treatment groups. However, the decreases in lesions were not similar enough to deem the 2 treatments equivalent. The participants graded both treatments acceptable and well tolerated although there was more desquamation at day 28 in the group receiving tretinoin (P=.002). The small sample size was a limitation of this study. In addition, 12 of 85 (14%) participants were lost to follow-up. The SA/LHA cream and tretinoin cream were both effective in reducing acne vulgaris. However, they were not found to be equivalent. Nevertheless, this study suggests that the SA/LHA formulation could be a treatment option to consider in patients with acne vulgaris who are intolerant to tretinoin.