Chronic hepatitis C is usually asymptomatic in children, but significant liver disease may occur. No large scale multi-center randomized controlled trial has been performed in this unique group. Peginterferon and ribavirin have been shown to be more effective than peginterferon alone in adults with hepatitis C and is the standard of care. However, ribavirin is a known teratogen, and preliminary data suggest that peginterferon alone may be as effective as combination therapy in children. We, therefore, have designed and initiated a randomized controlled trial to determine the efficacy and safety of peginterferon with and without ribavirin in children with chronic hepatitis C. An initial FDA Orphan Products Grant evolved into a fully funded NIH cooperative agreement with additional support from Roche Pharmaceuticals to establish a group of 11 Clinical centers and a Data Coordinating Center (PEDS C). Protocol development issues included an untreated control group, a compassionate combination treatment arm, blinding and unblinding strategies, and definition of early viral response. Other study elements were the selection of a central laboratory and the development of an Automatic Response System to facilitate patient registration and randomization. NIDDK sponsorship allowed for the integration of additional investigator-initiated studies not traditionally included in industry-sponsored trials including studies of the effects of treatment on body composition, growth and neurocognitive functioning. Finally, Ancillary Studies and Publication Policy Guidelines were developed, and a PEDS C Website was constructed. Since there have been few large-scale randomized controlled trials in pediatric gastroenterology, lessons learned from this trial may assist in the development of similar studies in this field.