Despite a great deal of prior research, the early pathogenic events in natural oral poliovirus 32 infection remain poorly defined. To establish a model for study, we infected 39 macaques 33 by feeding single high doses of the virulent Mahoney strain of wild type 1 poliovirus. Doses ranging from107 –109 34 TCID50 consistently infected all animals, and most monkeys receiving 108 or 109 35 TCID50 developed paralysis. There was no apparent difference in the 36 susceptibility of the three macaque species (rhesus, cynomolgus, and bonnet) used. Virus 37 excretion in stool and nasopharynges was consistently observed, with occasional viremia, and 38 virus was isolated from tonsils, gut mucosa, and draining lymph nodes. Viral replication proteins 39 were detected in both epithelial and lymphoid cell populations expressing CD155 in the tonsil 40 and intestine, as well as in spinal cord neurons. Necrosis was observed in these three cell types, 41 and viral replication in tonsil/gut was associated with histopathologic destruction and 42 inflammation. The sustained response of neutralizing antibody correlated temporally with 43 resolution of viremia and termination of virus shedding in oropharynges and feces. For the first 44 time, this model demonstrates that early in the infectious process, poliovirus replication occurs in 45 both epithelial cells (explaining virus shedding in the gastrointestinal tract) and 46 lymphoid/monocytic cells in tonsils and Peyer’s patches (explaining viremia), consistent with 47 previous studies of poliovirus pathogenesis in humans. Because this model recapitulates 48 human poliovirus infection and poliomyelitis, it can be used to study polio pathogenesis, 49 and to assess efficacy of candidate antiviral drugs and new vaccines.