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.