Current therapies for genital herpes have only partial efficacy. Helicase-primase inhibitors are novel, potent inhibitors of herpes simplex virus replication. This randomized trial assessed the safety and efficacy of ASP2151 for episodic therapy of recurrent genital herpes. Participants self-initiated with ASP2151 (100, 200, or 400 mg daily for 3 days), ASP2151 (1200 mg as a single dose), placebo for 3 days, or valacyclovir (500 mg twice daily for 3 days). The primary efficacy endpoint, time to lesion healing excluding aborted lesions, was analyzed using a proportional hazards model. Statistical significance was determined by P = .01. Of 695 adults enrolled, 437 experienced a recurrence and received study drug. Median time for lesion healing excluding aborted lesions was 139.8 hours with placebo, 119.6 hours with ASP2151 (100 mg; hazard ratio [HR], 1.40; P = .065), 106.2 with ASP2151 (200 mg; HR, 1.40; P = .081), 115.9 with ASP2151 (400 mg; HR, 1.25; P = .25), 102.1 with ASP2151 (1200 mg; HR, 1.72; P = .007), and 113.9 with valacyclovir (500 mg twice daily; HR, 1.42; P = .077), indicating improvement in all treatment groups except ASP2151 (400 mg). Incidence of treatment-emergent adverse events was similar across groups. Three-day or single-day courses of ASP2151 appear to be effective and safe options for treatment of episodes of recurrent genital herpes. NCT00486200.