Infection of rhesus macaques with simian immunodeficiency virus (SIV) is the preferred animal model for the development and testing of human immunodeficiency virus (HIV) vaccines, and animals protected from SIV challenge by live attenuated vaccines are an invaluable tool for determining immune correlates of protection. The acute phase of SIV infection, in which immune responses are most critical for slowing disease progression, occurs within the first 4 weeks of exposure. The small window of time available for observing critical immune responses makes obtaining adequate blood samples with sufficient frequency difficult. This study is the first to apply a previously reported nonhuman primate (NHP) tether system to study viral immunology. The use of the tether allows for frequent blood sampling without using restraints or sedation, thereby reducing the potentially confounding physiological changes induced by stress. We performed comparative analysis of acute phase immune responses in vaccinated and unvaccinated animals challenged with SIV-mac251. Our results demonstrate live attenuated vaccine-induced protection, which is associated with small increases in the cytotoxic T-cell (CTL) response to immunodominant epitopes, but not with increases in antibody titers. Additionally, vaccination was shown to establish a pool of antigen-specific CD8+ memory cells available for expansion after challenge. The confirmatory nature of these data indicates the validity of using the tether system for evaluation of acute phase anti-SIV responses and can be applied to the study of immune responses in other viral infections in which frequent sampling in small windows of time would be useful.