Pichinde virus produced a fatal infection in adult MHA hamsters but not LSH hamsters after intraperitoneal inoculation. After footpad inoculation, an 8-day swelling response was observed in LSH but not MHA hamsters; however, both strains survived infection by this route. Examination of the kinetics of viral replication in the two hamster strains inoculated by the two routes revealed a correlation between infectious centers and natural killer activity in cells obtained from spleens and popliteal lymph nodes. A subpopulation of cytolytic and infected cells which sedimented at about 3.0 to 4.5 mm/h in albumin gradients was found in greater numbers in MHA than in LSH hamsters. These data suggest that one factor contributing to the fatal outcome of Pichinde virus infection in MHA hamsters is the presence of excessive numbers of splenic target cells which possess properties of natural killer cells.