5-Fluorouracil (5-FU) cream is indicated for the treatment of actinic keratoses (AKs). It generally is applied across a broad area of skin rather than to specific AKs. It has been observed that when 5-FU is applied to the skin, not only do clinically apparent AKs become irritated, erythematous, and/or scaly, but subclinical sun damage also becomes clinically visible. In this small prospective study, 5-FU cream was applied to the faces of 19 participants (12 female, 7 male) between the ages of 35 and 55 years with no medical history of AKs or nonmelanoma skin cancers to determine if subclinical lesions could be identified and treated. The results showed that 100% (19/19) of participants in this study with no clinically apparent AKs had a positive reaction to 5-FU cream, indicating that they had subclinical sun damage that became clinically apparent. Because 5-FU cream is useful for the treatment of clinically apparent actinic lesions, it is believed that subclinical sun damage also is treated.