The sap of the plant Euphorbia peplus is a traditional remedy for skin conditions, including actinic keratosis. The active constituent of the sap is ingenol mebutate (ingenol‐3‐angelate), formerly known as PEP005. This randomized, double‐blind, vehicle‐controlled, phase IIa study investigated the safety (and secondarily the efficacy) of two applications of ingenol mebutate gel in 58 patients with biopsy‐confirmed actinic keratosis. Five preselected lesions were treated with ingenol mebutate gel, 0.0025%, 0.01% or 0.05%, or vehicle gel, on days 1 and 2 (Arm A) or days 1 and 8 (Arm B). There were no significant differences in tolerability or efficacy between Arms A and B. Treatment was well tolerated. The most common local skin responses were dose‐related erythema, flaking/scaling/dryness and scabbing/crusting. Efficacy was greatest with ingenol mebutate gel, 0.05%, which resulted in complete clinical clearance of 71% of treated lesions (P < 0.0001 vs vehicle gel). In addition, 67% of patients treated with ingenol mebutate gel, 0.05% had clinical clearance of at least four of five treated lesions (P = 0.0185 vs vehicle gel). Ingenol mebutate gel is being developed as a short‐course topical therapy for actinic keratosis and non‐melanoma skin cancer.