Topical fluorouracil is currently approved for the treatment of actinic keratosis (AK) and is often used prior to or following cryosurgery as interval therapy in patients with severe AK lesions. No randomized, controlled studies are available to confirm anecdotal evidence suggesting pretreatment with fluorouracil is beneficial. This prospective, randomized, double-blind, vehicle-controlled study evaluated the effect of pretreatment with 0.5% fluorouracil cream (FC; Carac) or a vehicle cream (VC) once daily for 7 days to the face plus scalp, ears, neck, and/or lips in patients with > or = 5 visible or palpable AKs on the face prior to cryosurgery. Efficacy was determined by evaluating AK reduction and clearance (complete lack of AK lesions in the treatment area) at 4 weeks follow-up. Statistically significant decreases from baseline number of AKs were observed on all treatment areas in both groups. However, the mean number of facial AKs was significantly lower in the FC group at each treatment cycle (p = .011). No serious adverse events were considered related to treatment.