Background: Actinic keratoses (AKs) are common and may progress to squamous cell carcinoma (SCC). While cryotherapy is the most commonly used treatment for AKs, it is only suitable for treating a few lesions at a time. Topical medications such as 5-fluorouracil (5-FU) allow for more generalized treatment of AKs in the setting of multiple lesions. Objective: To evaluate and discuss clinical trials examining the efficacy of 5-FU cream formulations (0.5% and 5%), as 5% 5-FU has four times greater systemic absorption. Methods: We conducted Pubmed and Embase searches (1965 to 13 April 2009) to find studies evaluating the efficacy of 5-FU cream monotherapy (0.5% and 5%) in treating multiple AKs of the face and scalp. We only included studies employing standard treatment regimens (as per the US FDA), with an endpoint of complete clearance. Results: Nine studies met our criteria. At 4 weeks post-treatment, complete clearance rates of 0.5% and 5% 5-FU ranged from 16.7% to 57.8% and 43% to 100%, respectively. As the various studies employed different measurements of tolerability, we were unable to pool this data. In the only split-face study comparing both formulations, both treatments produced equivalent rates (43%) of complete clearance, but 5% 5-FU had higher rates of adverse events. Conclusions: Despite evidence suggesting the superior efficacy of 5% 5-FU over 0.5% 5-FU, high-powered clinical trials comparing both treatments are lacking. Furthermore, tolerability rates between formulations warrant further examination given the possible enhanced systemic absorption of 5% 5-FU over 0.5% 5-FU. Such studies will enable dermatologists to appropriately balance the risks and benefits of each respective treatment to provide optimal solutions to patients with multiple AKs.