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To date, there is no consensus on the treatment of actinic keratosis (AK). Current national and international guidelines state no clear recommendations for the best choice of therapy. To determine the most effective treatment in terms of lesion reduction, costs and patient satisfaction topical treatment with 0.015% ingenol mebutate gel, 5% 5-fluorouracil cream, 5% imiquimod cream and photodynamic therapy were compared in a prospective randomized controlled multi-centre study. Patients older than 18 years with a Fitzpatrick skintype I-IV, with 5 AK’s Olsen class I-III in an area of minimal 25 cm2 and maximal 100 cm2 , localized in the head and neck area were included in the study. In total 624 were included in the Dermatology departments of the Maastricht University Medical Centre, Catharina hospital Eindhoven, Zuyderland Medical Centre Heerlen and VieCuri Medical Centre Venlo/Venray. Primary outcome measure is treatment success, defined as the proportion of participants with ≥ 75% reduction of the number of AK lesions in the treatment area at 12 months post final treatment compared to baseline. Secondary outcome is treatment success at 3 months post final treatment, cost-effectiveness, side effects, patient satisfaction, cosmetic outcome and treatment compliance.