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The aim of this study was to evaluate the impact of common psychiatric disorders on treatment completion of antiviral therapy prescribed to a series of hepatitis C virus (HCV) positive US veterans.Clinical experience suggests that preexisting psychiatric conditions may adversely affect the ability to tolerate combination antiviral therapy in patients with HCV infection.We performed a retrospective chart review of 130 HCV positive veterans treated with combination antiviral therapy [interferon (IFN)/ribavirin] at VA San Diego from 2000 to 2004. We examined baseline psychiatric and substance use diagnoses, as well as demographic and comorbid medical disease variables for all patients started on treatment.Thirteen percent of patients in our cohort required treatment discontinuation for neuropsychiatric adverse effects. There was no association between treatment completion and any specific psychiatric diagnosis, baseline use of antidepressants, history of substance abuse/dependence, or combined psychiatric and substance use diagnoses for patient groups receiving either standard or pegylated IFN plus ribavirin therapies. Psychiatric and substance use disorders were not associated with dropout due to neuropsychiatric adverse effects. Baseline comorbid medical disorders also did not predict treatment completion. However, higher body weight did predict likelihood of treatment completion, especially for those ≥100 kg compared with thinner subjects (odds ratio=2.90; P=0.037).In this cohort of veterans, prior psychiatric or substance use history did not predict completion of recommended IFN/ribavirin treatment. These findings suggest that a larger pool of veterans with psychiatric or substance use disorders may be considered candidates for antiviral therapy when provided with multidisciplinary support.