Several formulations and concentrations of topical fluorouracil have received US Food and Drug Administration (FDA) approval for the treatment of actinic keratosis (AK). The most commonly used are the fluorouracil 5% and 0.5% creams. In clinical trials, these formulations have demonstrated a marked ability to partially and completely eradicate AK lesions. Application site irritation, erythema, and burning are common side effects of both formulations, but comparative data suggest that the fluorouracil 0.5% cream is more cost-effective and may be safer, more tolerable, and as efficacious as fluorouracil 5% cream.