Infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease in the United States. Chronic hepatitis B and C virus infections were added to the nationally notifiable diseases list in 2003. Approximately 3.2 million persons in the United States have chronic HCV infection. The most common risk factor for HCV infection is illicit drug use (specifically injection-drug use [IDU]), although approximately one third to one half of cases have no identified risk factor. Because approximately 80% of acute HCV infections are asymptomatic and no serologic markers for recent infection exist, distinguishing recent from distant infection based on serology alone is challenging and establishment of national HCV infection incidence is difficult. CDC provides funding to enhance surveillance for HCV infection and other forms of viral hepatitis in New York State (NYS) and seven other areas. One project of enhanced surveillance is to identify those HCV infections most likely to have been acquired recently. Since January 2006, NYSDOH has prioritized follow-up of positive laboratory markers for HCV infection among persons aged <30 years because they are more likely to be newly infected than older persons. In February 2007, NYSDOH detected a cluster of HCV infections among persons in this age group by using the prioritized algorithm. This report describes the subsequent investigation by NYSDOH and the Erie County Department of Health (ECDOH), which identified a group of patients with histories of IDU who were linked through a single high school that all the patients had attended at some time. The findings demonstrate how targeted enhanced surveillance can effectively detect clusters and outbreaks and guide appropriate interventions.