BACKGROUND Topical diclofenac and imiquimod have been reported to be effective in the treatment of actinic keratosis, but a study to compare these two drugs has not been reported yet. OBJECTIVE To compare the efficacy and safety of topical 3% diclofenac gel plus hyaluronic acid and 5% imiquimod cream in the treatment of actinic keratosis. METHODS Forty-nine patients with actinic keratosis were enrolled in this randomized comparative open-label study. Twenty-four patients applied 3% diclofenac gel once a daily to their lesions, while the other 25 patients were treated with a 5% imiquimod cream three times a week for 12 weeks. Patients were examined before treatment and every month of the treatment. Assessments were made by investigators according to the Investigator and the Patient Global Improvement Indices (IGII) and (PGII). RESULTS According to the IGII results, a complete response was observed in 12% of the diclofenac group and 22% of the imiquimod group. For the PGII scores, a complete response was observed in 28% of the diclofenac group and 23% of the imiquimod group. There were no significant differences between the two groups (p > 0.05). Both treatments were well tolerated, with most adverse events related to skin. CONCLUSION The two drugs were found to be equally effective and safe in the treatment of actinic keratosis but complete remission was very low. Therefore, topical treatments with these two drugs were not seen to be completely effective, and combined therapies and further studies are needed.