In a double-blind, randomized, patient-initiated treatment study at five medical centers, 301 immunocompetent patients experiencing a recurrence of herpes labialis were treated with topical 15% idoxuridine (IDU) in dimethyl sulfoxide (DMSO), 80% DMSO control solution, or 2% DMSO control solution. IDU did not prevent the development of lesions but significantly accelerated lesion resolution in comparison with the combined control groups. For the total population, the mean duration of pain was reduced by 1.3 days (35%, P = .01) and the mean healing time to loss of crust by 1.7 days (21%, P = .004). Analysis of subpopulations revealed that the beneficial activity of the treatment was concentrated among the patients who began treatment in the prodrome or erythema lesion stage. For these patients, the mean duration of pain was reduced by 1.8 days (42%, P = .08) and the mean healing time to loss of crust by 3.3 days (38%, P less than .001). If only patients with classic herpes lesions (vesicle, ulcer, or crust formation) were considered, there was a greater drug effect on the duration of pain (reduction by 2.6 days, 49%; P = .03) and the mean healing time to normal skin was significantly shortened (reduction by 2.3 days, 23%; P = .004). Adverse reactions to the medication were minimal.