OBJECTIVES: Ingenol mebutate gel is a recently developed, topical, 2 or 3 days patient-administered AK therapy.  The objective was to compare the cost-effectiveness of ingenol mebutate gel with diclofenac gel and other available therapies for the first-line treatment of AK in adult patients, from the perspective of the National Health Service (NHS) in Scotland. METHODS: A cost-utility analysis was conducted using a decision tree approach to calculate the costs and benefits of different treatment strategies for AK over a 12-month time horizon. Data on the relative efficacy of treatment was derived from a systematic review of RCTs and a subsequent mixed-treatment comparison (MTC). Utility scores and resource use data were obtained from published sources. Due to the uncertainty surrounding the impact of AEs on HRQoL and costs, AEs were modelled in a scenario analysis. RESULTS: In the primary comparison, ingenol mebutate 150 mcg/g gel and 500 mcg/g gel were associated with ICERs of £44 and £114 per QALY gained, respectively compared with diclofenac (3%) for 8 weeks and £36 and £74, respectively compared with diclofenac (3%) for 12 weeks. In the secondary comparisons, ingenol mebutate 150 mcg/g gel and 500 mcg/g gel were associated with ICERs of £47 and £134, respectively compared with 5-FU/salicylic acid (0.5%/10%) cutaneous solution and dominated cryotherapy (i.e. were cheaper and more effective). Ingenol mebutate 150 mcg/g gel and 500 mcg/g gel were cheaper and less effective than 5-FU (5%) cream. Ingenol mebutate 150 mcg/g gel, but not  ingenol mebutate 500 mcg/g gel, was cost-effective assuming a decision making willingness-to-pay threshold of £20,000/QALY (for one additional QALY gained, there would be an incremental cost of £26,525 incurred for 5-FU (5%)  cream vs ingenol mebutate gel). CONCLUSIONS: Ingenol mebutate gel is a fast-acting, convenient and, relative to most comparators, cost-effective therapy for the first-line treatment of AK.