The long-term effects of preemptive antiviral therapy on fibrosis progression in liver transplant recipients with hepatitis C virus (HCV) were examined in a cohort of consecutive liver transplant recipients who received preemptive antiviral therapy for 48 weeks (95% were virologic nonresponders). Control patients were transplanted during this same period but did not receive preemptive therapy. Patients were followed to the date of last biopsy and censored at the time of subsequent HCV treatment. Eighty-six patients surviving ≥90 days were included. Treated and control patients were similar, except that treated patients had longer histological follow-up (60 versus 50 months), a lower median Model for End-Stage Liver Disease score at liver transplant (17 versus 23), and a shorter median length of hospital stay (6 versus 9.5 days). In the uncensored analysis, the cumulative probability of a Batts-Ludwig fibrosis score ≥ 2 at 48 months post–liver transplant was 22% in the preemptive therapy group and 49% in the nonpreemptive therapy group (P = 0.08). In multivariate analysis, preemptive therapy was associated with a 48% reduced risk of a fibrosis score ≥ 2 (hazard ratio = 0.52, 95% confidence interval = 0.24-1.12, P = 0.09), but this failed to achieve statistical significance. Receipt of preemptive therapy was associated with a delay in subsequent HCV therapy for moderate to severe disease (fibrosis score ≥ 2 or moderate necroinflammatory activity) with a median time of 36.3 months versus 20.3 months in the preemptive and nonpreemptive groups (P = 0.004). We conclude that preemptive antiviral therapy in virologic nonresponders delays the time to subsequent HCV treatment and may confer a reduced risk of fibrosis progression. Further study of preemptive antiviral therapy is warranted. Liver Transpl 14:1491–1497, 2008. © 2008 AASLD.