Actinic keratoses are common in older individuals and topical immunotherapy is an important treatment when multiple lesions are present. To assess the efficacy of 5-fluorouracil in treating actinic keratoses, a systematic review of randomized, vehicle-controlled trials was performed. Percentages of 5-fluorouracil and vehicle responders were determined by absolute clearance and mean percent reduction in lesion count. Four trials with 399 and 269 participants in active treatment and vehicle groups, respectively, were evaluated. After 4 weeks of treatment, total clearance and mean lesion count reduction were 52.6 and 90.2% in the treatment group versus 0.85 and 28.3% in the vehicle group, respectively. Topical 5-fluorouracil is efficacious in treating actinic keratoses; however, vehicle responses warrant further investigation of study design and disease severity scales.