Background: Photodynamic therapy (PDT) has not been compared with topical 5-fluorouracil (5-FU) in the treatment of epidermal dysplasia. Objective: The purpose of this study was to assess the efficacy and tolerability of these two treatment modalities in 17 patients with actinic keratoses on the backs of the hands. Methods: Each patient’s right and left hands were randomized to receive either a 3-week course of topical 5-FU applied twice per day or PDT using topical 5-aminolevulinic acid (5-ALA) and then, after 4 hours, irradiation with an incoherent light source consisting of a 1200 W metal halogen lamp emitting red light (580 to 740 nm). Each hand randomized for PDT received 150 J/cm². The observed median fluence rate was 86 mW/cm² (interquartile range, 53 to 100 mW/cm²). All patients were reviewed at 1, 4, and 24 weeks after starting treatment. Results: Fourteen of 17 patients (82%) completed the study. The mean lesional area treated with topical 5-FU decreased from 1390 mm² (standard deviation [SD], 1130) to 297 mm² (SD, 209). This represents a mean reduction in lesional area of 70% (confidence interval [CI], 61%-80%). The mean lesional area treated with topical PDT decreased from 1322 mm² (SD, 1280) to 291 mm² (SD, 274), representing a mean reduction in lesional area of 73% (CI, 61%-84%). The reduction in lesional area elicited by the two treatment methods was similar (CI, –25% to 17%). There was no statistically significant difference between the treatment methods in overall symptom scores for pain and redness. Conclusion: One treatment with PDT using topical 5-ALA appears to be as effective and well tolerated as 3 weeks of twice-daily topical 5-FU, a cheap and widely available alternative. (J Am Acad Dermatol 1999;41:414-8.)