We studied the ability of a molecularly cloned SIVHIV chimeric virus, SHIV33, to infect and cause disease in rhesus neonates. SHIV33 consists of the SIVMAC239 genetic background and HIV-1-SF33 envelope and induces persistent infection in juvenile rhesus macaques, but no disease after more than one year after inoculation. We tested the hypothesis that the developing neonatal rhesus immune system would permit virus to persist and disease to progress more rapidly in newborn than in juvenile or adult rhesus macaques infected with SHIV33. Four rhesus neonates were inoculated intravenously with a moderate dose (100 tissue culture infectious doses) of SHIV33. All four neonates developed a low level transient plasma viremia, but persistent, moderate to low levels of cell-associated viremia relative to two neonates inoculated intravenously with molecularly cloned, pathogenic SIVMACc239. All four SHIV33-infected animals developed strong antiviral antibody responses by 8 weeks pi (similar to SHIV33-infected juvenile rhesus macaques) and all remain healthy after more than 11 months after inoculation. In contrast, two of two SIVMAC239-infected neonates developed persistent high cell-free and cell-associated virus load in peripheral blood and weak anti-viral antibodies. One of the SIVMAC239-infected neonates was euthanatized at 34 weeks after inoculation with pathologic lesions diagnostic for SAIDS; the other SIVMAC23 infected neonate remained alive with no significant clinical disease. These results indicate that (i) persistent cell-associated viremia is not sufficient to cause rapid disease (< 6 months after inoculation) in neonates, and (ii) rhesus neonates are capable of developing rapid antiviral antibody responses even when infected at birth with a lentivirus which establishes persistent infection.