OBJECTIVE In the Diabetes Virus Detection and Intervention trial, antiviral treatment with pleconaril and ribavirin decreased the decline, compared with placebo, in endogenous C-peptide 1 year after diagnosis of type 1 diabetes (T1D) in children and adolescents. This article reports the results 2 and 3 years after diagnosis.RESEARCH DESIGN AND METHODS This was a multicenter, randomized, placebo-controlled (1:1) trial of 96 children and adolescents aged 6-15.9 years newly diagnosed with T1D. Antiviral treatment (pleconaril and ribavirin) or placebo was given for 6 months from diagnosis, and participants were followed for 3 years. The primary outcome was residual C-peptide secretion, reported as the area under the curve (AUC), assessed by 2-h mixed-meal tolerance test. Secondary outcomes included insulin doses and HbA1c.RESULTS At the 3-year follow-up, 75 participants attended. At 2 years, the mean +/- SD AUC for C-peptide in the placebo group was 0.27 +/- 0.33 compared with 0.34 +/- 0.37 in the pleconaril and ribavirin group. After 3 years, the AUC had decreased to 0.17 +/- 0.23 and 0.25 +/- 0.34, respectively. There was no statistically significant difference between the groups. The groups were also comparable with regard to secondary end points.CONCLUSIONS The decreased reduction in C-peptide levels after antiviral treatment is no longer present after 2 or 3 years. Further investigations are needed to explore options to use antiviral treatment in the prevention and treatment of T1D.