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Actinic keratoses (AK) are pre-neoplastic lesions related to an excessive ultraviolet exposure that represent an emerging issue in the area of skin diseases which undergo high risk for developing squamous cell carcinoma (SCC). In this open study, we tested the safety efficacy profile of sequential ablative laser and Ingenol Mebutate gel (IngMeb). Thirteen patients with a total of 99 lesions were selected for this open study. When multiple lesions on the same area were found, the treatment area was split in half. In one group, fractional CO2 laser microablative treatment was performed the day before three daily applications of IngMeb 150 lg/g; the other group received IngMeb without previous laser ablation. Fifty-six lesions were treated with laser and IngMeb and a total of 43 lesions in the second group were treated with IngMeb alone. Results at the 12-week follow-up visit showed that a clearance rate of 50/56 (89.2%) had been achieved. On the side that was not pre-treated with laser, 31 out of 43 lesions were cleared (72.1%). In our opinion, ablative fractional laser treatment could improve topical treatment of AKs, or provide a further therapeutic option for resistant patients.