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Daily antiviral therapy with famciclovir and valacyclovir has been shown to be effective in reducing both symptomatic and asymptomatic reactivation of herpes simplex virus type 2 (HSV-2) when compared to placebo. However, few comparative studies between the 2 antivirals have been performed.To compare the clinical and virologic effects of famciclovir and valacyclovir administered as daily suppressive therapy for persons with genital herpes.Two randomized, double-blind, placebo-controlled studies comparing daily famciclovir 250 mg bid with valacyclovir 500 mg qd were performed. Study 1 randomized 320 participants and compared the clinical effect of the drugs given for 16 weeks, and study 2 enrolled 70 HSV-2 seropositive subjects and compared the virologic effect of the drugs given for 10 weeks.In study 1, the time to first recurrence was similar in famciclovir and valacyclovir recipients, hazard ratio (HR) 1.17 (95% CI, 0.78–1.76), but time to first virologically confirmed recurrence was shorter among famciclovir recipients, HR = 2.15 (95% CI, 1.00–4.60). In study 2, HSV was detected on 3.2% of days among famciclovir recipients and 1.3% of days among valacyclovir recipients, relative risk 2.33 (95% CI, 1.18–4.89).Valacyclovir appear to be somewhat better than famciclovir for suppression of genital herpes and associated shedding. Further comparative trials of antiviral drugs for various indications should be performed as acyclovir and penciclovir appear to have different ability to abrogate HSV reactivation.