Background Ingenol mebutate gel is a novel, field-directed topical treatment for actinic keratosis (AK). Most pivotal studies have targeted Western populations. No clinical study has been conducted to investigate its efficacy and safety in Asian populations. Objectives To evaluate the efficacy and safety of ingenol mebutate gel for treating AK of face/scalp and trunk/extremities in a large Asian (Korean) population. Methods In this multi-centre, open-label, interventional, parallel group, prospective phase 4 study (PERFECT, NCT02716714), the eligible subjects were allocated into either the face/scalp or the trunk/extremities group, according to their selected treatment area location. After application of ingenol mebutate gel, the subjects were followed-up for 6 months. The primary efficacy endpoint was complete clearance (CC) rate of AK lesions in the selected treatment area on Day 57. The quality of life was evaluated using Skindex-29. Safety endpoints included local skin responses, scar, pigmentation, pain, and adverse events. Results In total, 78.1% (95% CI: 66.86–86.92%) of subjects had CC on day 57, with 76.6% (95% CI: 64.31–86.25%) in face/scalp group and 88.9% (95% CI: 51.75–99.72%) in trunk/extremities group. Among them, the CC rate was sustained in 88.9% (48/54 subjects, 95% CI: 77.37–95.81%) on Month 6. The local skin responses significantly increased 1 day after the treatment compared to baseline, and decreased afterwards. Among the total subjects, 7.8% (6/77 subjects) had hyperpigmentation on the application area. Scars were not reported. Conclusions Ingenol mebutate is effective for the treatment of AK in Asians, with tolerable safety profiles. This article is protected by copyright. All rights reserved.