Rationale: Human herpesviruses Epstein-Barr virus and cytomegalovirus are frequently detectable in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and could contribute to disease pathogenesis. Objectives: With the goal of inhibiting herpesvirus replication, we tested the safety and tolerability of adding valganciclovir to standard IPF therapy (pirfenidone). Methods: We performed a single-center, Phase I, double-blind, randomized, placebo-controlled trial comparing valganciclovir 900 mg daily with placebo in patients with IPF with serologic evidence of prior Epstein-Barr virus and/or cytomegalovirus infection who were tolerating full-dose pirfenidone (2,403 mg/d). Subjects were randomized to valganciclovir or placebo 2:1 for 12 weeks of active treatment with off-treatment follow-up for up to 12 months. The primary safety endpoint was the number of subjects discontinuing the study drug before completing 12 weeks of treatment. Results: Thirty-one subjects with IPF were randomized to valganciclovir (n = 20) or placebo (n = 11). All subjects completed assigned therapy except one subject in the valganciclovir group, who discontinued the study drug after developing a rash. The total number of adverse events was similar between study groups. In a prespecified analysis of secondary physiologic endpoints, we observed a trend toward improved forced vital capacity from randomization to Week 12 in valganciclovir-treated subjects (-10 ml; interquartile range [IQR], -65 to 70 ml) versus placebo-treated subjects (40 ml; IQR, -130 to 60 ml), which persisted through 12 months of follow-up. Conclusions: Valganciclovir is safe and well tolerated as an add-on therapy to pirfenidone in patients with IPF. Clinical trial registered with ClinicalTrials.gov (NCT02871401).