Essential mixed cryoglobulinemia in humans is strongly associated with chronic hepatitis C virus infection. It remains controversial whether liver injury in hepatitis C is primarily attributable to direct viral cytopathic effect or to an immune-mediated response. We characterized the role of cryoglobulinemia in the development of liver disease in thymic stromal lymphopoietin (TSLP) transgenic mice that produce mixed cryoglobulinemia and develop hepatitis. The role of immune complexes in this animal model was evaluated using techniques of light, immunofluorescence, and electron microscopy. To assess the role of Fc receptor engagement in mediation of the disease, TSLP transgenic mice were crossbred with mice deficient for immunoglobulin-binding receptor gamma IIb (FcgammaRIIb). Livers from the TSLP transgenic animals showed mild to moderate liver injury, minimal to mild fibrosis, and deposition of immunoglobulin around the portal tracts. TSLP transgenic mice deficient in inhibitory FcgammaRIIb had more severe hepatitis and accelerated mortality. TSLP-associated hepatitis bears strong similarity to hepatitis C virus-related hepatitis as it occurs in humans, making this a valuable model system of chronic hepatitis and fibrosis to study therapies aimed at manipulating immune responses. Periportal immune complex deposition may play an important role in the pathogenesis of hepatitis occurring in the setting of systemic cryoglobulinemia.