We performed a pilot study examining the safety and tolerability of valacyclovir in veterans with herpes simplex virus type 2 and hepatitis C virus (HCV) coinfection. We performed a randomized double-blind, placebo-controlled, crossover clinical trial in U.S. veterans with genotype 1 HCV/herpes simplex virus type 2 coinfection. Patients were randomized 1:1 in blocks of 10 to receive either 1 g twice-daily valacyclovir or matching placebo for 8 weeks followed by a 2-week washout phase with daily placebo. The alternate therapy (valacyclovir or placebo) was given for an additional 8-week period. Safety assessments were performed every 2 weeks. Changes in HCV RNA and alanine aminotransferase (ALT) were estimated using linear mixed models (SAS Proc Mixed). Thirty patients were enrolled. Valacyclovir was not associated with toxicity or adverse events. ALT levels declined 6% to 10%; mean HCV RNA levels were reduced 24% (1.3 million IU/mL [0.21 log10 IU/mL]) during the valacyclovir phase (P = 0.08) with no carryover effect observed (P = 0.21). Valacyclovir 1 g twice daily showed no evidence of hepatotoxicity in U.S. veterans with hepatitis C. A modest reduction in serum levels of ALT and plasma levels of HCV RNA was observed.