L-lysine has an inhibitory effect on the multiplication of herpes simplex virus in cell cultures. We have evaluated the prophylactic effect of L-lysine monohydrochloride 1000 mg daily on recurrent herpes simplex labialis in 65 patients in a double-blind, placebo-controlled, crossover study. After 12 weeks of lysine treatment the patients shifted to placebo treatment for a similar period. On the whole, lysine prophylaxis had no effect on the recurrence rate of herpes simplex. However, significantly more patients were recurrence-free during lysine than during placebo treatment (p = 0.05), suggesting that certain patients may benefit from prophylactic lysine administration. In the herpes lesions described, lysine had no effect on the rate of healing or on the appearance of the lesions at their worst.