The interferon alpha (IFN-alpha) response of rhesus macaques was investigated during primary infection with pathogenic and attenuated simian immunodeficiency virus (SIV). IFN-alpha was detected in the serum of animals as early as day 4 after inoculation of SIVmac251, but remained barely detected in animals infected with the attenuated virus SIVmac251 delta nef. The peak of IFN-alpha secretion preceded that of antigenemia in animals infected with pathogenic virus, indicating that the IFN-alpha response did not prevent viral spread. In addition, elevated levels of IFN-alpha 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-alpha 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-alpha-producing cells were numerous in the LNs of animals that had a high viral burden. Taken together, these findings indicate that the IFN-alpha response is unable to contain the initial burst of SIV replication.