Simian immunodeficiency virus (SIV) infection of natural-host species, such as sooty mangabeys (SMs), is characterized by a high level of viral replication and a low level of generalized immune activation, despite evidence of an adaptive immune response. Here the ability of SIV-infected SMs to mount neutralizing antibodies (Nab) against autologous virus was compared to that of human immunodeficiency virus type 1 (HIV-1) subtype C-infected subjects. While high levels of Nab were observed in HIV-1 infection, samples obtained at comparable time points from SM exhibited relatively low titers of autologous Nab. Nevertheless, SM plasma with higher Nab titers also contained elevated peripheral CD4⁺ T-cell levels, suggesting a potential immunologic benefit for SMs. These data indicate that AIDS resistance in these primates is not due to high Nab titers and raise the possibility that low levels of Nab might be an inherent feature of natural-host SIV infections.