BACKGROUND: Actinic keratosis (AK) is a common skin condition treated by dermatologists
however, the effectiveness, superiority, and potential side effects of current treatment protocols are still debated. AIM: This study aimed to compare the effectiveness and safety of 5% fluorouracil topical cream and 1% niacinamide topical gel in patients with AK. METHODS: In a randomized clinical trial, 26 patients with 95 AK lesions were assigned to receive either 5% fluorouracil topical cream twice daily for 4 weeks or 1% niacinamide topical gel twice daily for 3 months. Photography and dermoscopy before and after treatment were used to evaluate the outcomes. RESULTS: The study included 26 patients who underwent randomization and treatment. Analysis of the improvement response after treatment through photography and dermoscopy scores, as well as patients' perspectives, showed that the fluorouracil group had significantly better outcomes than the niacinamide group. However, treatment complications including burning, itching, and erythema were significantly more frequent in the fluorouracil group than in the niacinamide group. CONCLUSIONS: Although 5% fluorouracil cream is more effective than 1% niacinamide gel in treating AK lesions, it is also associated with more frequent side effects.