BACKGROUND Photodynamic therapy with methyl aminolevulinate (MAL-PDT) and ingenol mebutate gel (IMB) are approved therapeutic options for multiple actinic keratoses (AKs). OBJECTIVE The aim of this intraindividual, split-face, randomized clinical trial was to compare treatment outcomes of MAL-PDT and IMB. METHODS Two symmetrical contralateral areas with a similar number of AKs were selected and randomly assigned to 3 days of an IMB treatment cycle or a single session of MAL-PDT. The next day, the local skin reaction (LSR) score was registered. The patients scored pain and time to healing of the treatment area. RESULTS After 90 days, the complete remission rate of lesions, the number of patients with complete remission of all lesions, cosmetic outcome, and patient preference were assessed. CONCLUSION According to our results, IMB and MAL-PDT had a similar efficacy, but the cosmetic outcome was superior with MAL-PDT. Pain was higher with PDT, but LSR was more severe and time to healing was longer with IMB. Patients preferred MAL-PDT.