Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are important causes of morbidity and mortality in the United States. Because HBV and HCV are transmitted efficiently percutaneously, possible transmission in health-care settings is of particular concern. Public health investigations of cases of HBV and HCV infection suspected to be associated with health-care delivery play an essential role in identifying unsafe practices and controlling health-care-associated viral hepatitis transmission. However, these investigations are resource intensive, and frequently overwhelm health department resources. Over many years, the New York City Department of Health and Mental Hygiene (DOHMH) developed a systematic approach to guide investigation and public health response to case reports of acute HBV or HCV infection in patients whose infection was potentially associated with health-care delivery. In this approach, the least resource-intensive investigation components are conducted for each case, and decisions to expand the investigation to more resource-intensive components are guided by the likelihood that a single case report represents a cluster of health-care-associated infections (HAIs). This report describes the DOHMH approach in the context of two single case reports. Components of this approach might be useful to other health departments that are developing their own approaches to this type of investigation.