The course of Pichinde virus infection in two strains of hamsters, LVG and MHA, was studied by sequential frozen-section immunofluorescence and light and electron microscopy. The major destructive effects of the infection were in the spleen and liver. In the spleen, primary target cells were macrophages in the marginal zone of the white pulp with subsequent spread into elements of the red pulp. In the liver, there was Kupffer cell and hepatocellular infection. The extent of involvement correlated with the outcome of infection; more extensive and progressive necrosis occurred in the fatally infected MHA than in the LVG strain in which infection was self-limiting. In neither strain of animal was there demonstrable infection of lymphoid cells. Similarly, lesion sites did not have mononuclear inflammatory infiltrations which are characteristic of most viral infections. These findings suggested that, in contrast to the situation in other rodent arenavirus infections, the lesions in these hamsters were probably not consequences of immunopathologic host response but rather were a result of direct viral effects in concert with a genetically determined host susceptibility.