OBJECTIVES: To estimate the incremental cost-utility ratio (ICUR) for ingenol mebutate vs diclofenac 3% for actinic keratosis (AK) patient’s treatment on the face and scalp, and trunk and extremities, in Spain. METHODS: A hypothetical cohort of 73 aged AK patients was simulated for a 5-year time horizon with a Markov model. Duration of treatments was 3 days (face-scalp) and 2 days (trunk-extremities) for ingenol mebutate and 90 days (face-scalp and trunk-extremities) for diclofenac. Total clearances rates (42.24% and 34.07% for ingenol mebutate and 24.64% and 25.07% for diclofenac on face-scalp and on trunk-extremities, respectively) obtained from indirect mixed comparisons and adjusted according compliance were used as effectiveness measure. Annual recurrence rate (20%) derived from literature. The perspective of the Spanish National Health System (NHS) was choosen. Total cost estimation (€,2015) included: pharmaceutical cost (retail price VAT included with mandatory deduction), and dermatology visits cost (for adverse events and disease management).A 3% annual discount rate was applied for costs and outcomes. Utilities values (0.986 for AK and 1.00 for clearance) were used to derive quality-adjusted-life years (QALY). Several sensitivity analyses were performed to test model robustness. RESULTS: Ingenol mebutate showed higher effectiveness, with 0.192 incremental clearances and 0.011 incremental QALYs (face-scalp), and 0.129 incremental clearances and 0.007 incremental QALYs (trunk-extremities) compared to diclofenac. Total costs accounted were €551.50 and €622.27 (46% drug cost) for ingenol mebutate, compared to €849.11 and € 844.93 (54% drug cost) for diclofenac (for face-scalp and trunk-extremities, respectively). Ingenol mebutate versus diclofenac 3% was dominant on face-scalp and trunk-extremities AK treatment. Further, ingenol mebutate remained a dominant option in 96% (face-scalp) and 91% (trunk-extremities) of the 1,000 MonteCarlo simulations of probabilistic sensitivity analysis. CONCLUSIONS: Ingenol mebutate was a dominant strategy for Spanish NHS, compared to diclofenac 3%, for treatment of patients with AK both, face-scalp and trunk-extremities.