The role of serotonin in contributing to viral clearance has not been investigated in patients with chronic hepatitis C (HCV). In this prospective study we collected blood samples from 39 patients prior to and during antiviral therapy. Participants completed mood rating scales to monitor psychiatric symptoms, and serum serotonin and tryptophan levels were measured. Significant differences in serotonin levels were found between patients who achieved sustained viral responses (SVRs) and those who did not. Regression analysis revealed that serotonin was the only variable with a statistically significant relationship with antiviral therapy outcomes, even after controlling for other variables known to be associated with outcomes. Baseline serum serotonin levels, in combination with other variables such as degree of liver fibrosis, may be clinically useful for identifying patients in whom HCV can be cleared by antiviral therapy. Additional clinical predictors that could forecast treatment success are needed so that interventions to improve SVR rates, and reduce side effects, can be developed.