Tamiami virus was inoculated into its natural reservoir host, the cotton rat (Sigmodon hispidus), and the course of infection was followed by sequential organ titrations, frozen-section immunofluorescence, and light and electron microscopy. In animals infected at 2 days of age, there was an early lymphoreticular tropism with peak concentrations of virus and viral antigen in lymph nodes, splenic white pulp, thymus, and bone marrow at 16 days postinoculation. Megakaryocyte infection was early and pronounced. Viral antigen concentration peaked in liver and salivary glands at day 30 and in kidney, adrenal cortex, respiratory tract, and bladder epithelium at day 60-long after viral infectivity in these organs had disappeared. Central nervous system infection was only modestly productive of infectious virus, but viral antigen continued to increase in the brain until day 90 and then did not decline throughout the 360-day study. Reticuloendothelial hyperplastic foci were found late in some target organs, but there was never any histologic or ultrastructural evidence of cytonecrosis. Older animals were virtually uninfectable; therefore, this susceptibility of newborns and their slow termination of infection represent the key to virus transmission and perpetuation in nature. These aspects of viral natural history contribute to an understanding of human exposure to the pathogenic arenaviruses which exist in similar rodent niches.