Forty patients presenting with first episode genital herpes were randomly allocated to seven day treatment with oral acyclovir alone, placebo alone, oral acyclovir plus co-trimoxazole, or placebo plus co-trimoxazole. Patients receiving acyclovir had significantly shorter periods of viral shedding (p less than 0.001), pain (p = 0.03), and times to lesion healing (p less than 0.05). Averaged over all patients there was no evidence that co-trimoxazole affected any of the variables, though in women cotrimoxazole was associated with a shorter time to lesion healing (p less than 0.01). Furthermore, the combination treatment gave significantly shorter times to lesion healing than acyclovir alone, placebo alone, or placebo and co-trimoxazole (p = 0.01) and good trends elsewhere (external lesions and duration of pain). Neither drug was associated with any adverse events or toxicity or influenced the subsequent recurrence rate.