The interferon α (IFN-α) response of rhesus macaques was investigated during primary infection with pathogenic and attenuated simian immunodeficiency viruses (SIV). IFN-α was detected in the serum of animals as early as day 4 after inoculation of SIVmac 251, but remained barely detected in animals infected with the attenuated virus SIVmac 251 △nef. The peak of IFN-α secretion preceded that of antigenemia in animals infected with pathogenic virus, indicating that the IFN-α response did not prevent viral spread. In addition, elevated levels of IFN-α in the serum after the acute stage of infection was associated with persisting antigenemia. The analysis of lymph nodes (LNs) by in situ hybridization showed that, similar to the results obtained with peripheral blood, the induction of IFN-α in lymphoid organs was rapidly detected in animals infected with the pathogenic virus, but remained very limited in animals infected with the attenuated virus. Quantitation of the hybridization signal indicated that IFN-α-producing cells were more numerous in the LNs of animals that had a high viral burden. Taken together, these findings indicate that the IFN-α response is unable to contain the initial burst of SIV replication.