This prospective, parallel‐group, randomized, double‐blind, multicenter study compared the efficacy and safety of FV‐100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ). Patients, ≥50 years of age, diagnosed with HZ within 72 h of lesion appearance who had HZ‐associated pain, were randomized 1:1:1 to a 7‐day course of either FV‐100 200 mg QD (n = 117), FV‐100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically significant pain (CSP); pain scores; incidence and severity of post‐herpetic neuralgia (PHN); and times to full lesion crusting and to lesion healing. Safety was evaluated on the basis of adverse event (AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV‐100 200 mg, FV‐100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV‐100 200 mg, FV‐100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively. Adverse event and SAE profiles of the two FV‐100 and the valacyclovir groups were similar and no untoward signals or trends were evident. These results demonstrate a potential for FV‐100 as an antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and reduce the incidence of PHN compared with available treatments.