The timing of HIV dissemination to the central nervous system (CNS) has the potential to have important implications regarding HIV disease progression and treatment. The earlier HIV enters the CNS the more difficult it might be to remove with antiretroviral therapy. Alternatively, HIV may only enter the CNS later in the course of disease as a result of disruption of the blood-brain-barrier. We utilized the simian immunodeficiency virus (SIV) infection of rhesus macaques to evaluate the oral route of infection and the subsequent spread of SIV to the CNS during the acute infection phase. A high dose oral SIV challenge was utilized to ensure a successful infection and permit the evaluation of CNS spread during the first 1-14 days post-infection. Ultrasensitive nested PCR was used to detect SIV gag DNA in the brains of macaques at 1-2 days post-infection and identified SIV gag DNA in the brain tissues from three of four macaques. This SIV DNA was also present following perfusion of the macaque brains, providing evidence that it was not residing in the circulating blood but in the brain tissue itself. The diversity of the viral envelope V1-V2 region at early times post-infection indicated that the brain viral variants were similar to variants obtained from lymph nodes. This genetic similarity between SIV obtained from lymphoid and brain tissues suggests that the founder population of viral species entered and subsequently spread without any evidence of brain-specific SIV selection. The relatively rapid appearance of SIV within the CNS tissue following oral transmission may also occur during HIV transmission where it may impact disease course as well as representing a challenge for long-term therapies and future viral eradication modalities.