Resiquimod (R-848), a topically active immune response modifier, induced production of interferon-α and interleukin-12 in cultured blood mononuclear cells and decreased genital herpes recurrences in an animal model. In this study, 52 patients with frequently recurrent genital herpes applied topical resiquimod gel 0.01% (twice or thrice weekly) or 0.05% (once or twice weekly) or vehicle gel to herpes lesions for 3 weeks. During the 6-month observation period after treatment, median days to first recurrence in the pooled resiquimod group was 169 days, compared with 57 days for the vehicle group (P=.0058). In all, 32% of resiquimod-treated patients completed the observation period without a recurrence, compared with 6% of vehicle-treated patients (P=.039). Resiquimod 0.05% twice weekly produced dose-limiting inflammation at the lesion sites, but the other regimens were well tolerated. Application of resiquimod to genital herpes lesions appeared to reduce the frequency of recurrences