Foamy viruses (FV), retroviruses of the genus Spumavirus, are able to infect a wide variety of animal species and replicate in nearly all types of cultured cells. To identify the cells targeted by FV in the natural host and define the sites of viral replication, multiple organs of four African green monkeys naturally infected with simian FV type 3 were investigated for the presence of FV proviral DNA and viral transcripts. All organs contained significant amounts of FV proviral DNA. In addition to proviruses containing the complete transactivator genetaf,proviral genomes carrying a specific 295-bp deletion in thetafgene were detected in all monkeys. As in the case of human foamy virus the deletion leads to the formation of thebetgene that is regarded to be instrumental in the regulation of viral persistence. FV RNA was detected by RT-PCR andin situhybridization only in the oral mucosa of one monkey. No other samples contained detectable levels of viral transcripts. Histopathological changes were not observed in any of the tissue samples analyzed. Our results show that the natural history of FV is characterized by latent infection in all organs of the host and by minimal levels of harmless viral replication in the oral mucosa. The broad host cell rangein vivofurther encourages the development of FV-derived vectors for therapeutic gene delivery.