The generation of a new, cost-effective, non-primate, small-animal model would greatly facilitate research into hepatitis C virus (HCV) pathogenesis and the development of novel therapeutic and preventative technologies to control the increasing HCV threat to public health. Native HCV from patient plasma and HCV grown in cell culture (HCVcc) were used to inoculate adult tree shrews. Each animal was inoculated with one HCV genotype. Alanine aminotransferase (ALT) levels, HCV RNA and viral load were determined in the animals before and after inoculation. For native HCV, 16/18 inoculated tree shrews (89 %) became infected; 12/16 (75 %) of these animals became chronically infected, whilst infection was resolved in the remaining four (25 %). For HCVcc, infection occurred in 10/12 inoculated tree shrews (83 %) and chronic infection was observed in two of these animals. HCVcc from Huh7 cells showed a higher infectivity than that from HeLa cells. The animals inoculated with inadequate amounts of HCV were not infected in either native HCV or HCVcc experiments. Peak viral loads reached 10(3)-10(5) international units ml(-1) in chronically infected animals. ALT level changes reflected the normal fluctuation range in most animals. Thus, tree shrews without immunosuppression can be infected efficiently by native HCV and HCVcc when the animal is inoculated with an adequate amount of single-genotype HCV.