In vivo depletion of CD8⁺ T cells results in an increase in viral load in macaques chronically infected with simian immunodeficiency virus (SIVmac239Δnef). Here, the cellular and humoral immune responses associated with this transient period of enhanced viraemia in macaques infected with SIVmac239Δnef were characterized. Fourteen days after in vivo CD8⁺ T-cell depletion, two of six macaques experienced a 1–2 log₁₀ increase in anti-gp130 and p27 antibody titres and a three- to fivefold increase in gamma interferon-secreting SIV-specific CD8⁺ T cells. Three other macaques had modest or no increase in anti-gp130 antibodies and significantly lower titres of anti-p27 antibodies, with minimal induction of functional CD8⁺ T cells. Four of the five CD8-depleted macaques experienced an increase in neutralizing antibody titres to SIVmac239. Induction of SIV-specific immune responses was associated with increases in CD8⁺ T-cell proliferation and fluctuations in the levels of signal-joint T-cell receptor excision circles in peripheral blood cells. Five months after CD8⁺ T-cell depletion, only the two high-responding macaques were protected from intravenous challenge with pathogenic SIV, whilst the remaining animals were unable to control replication of the challenge virus. Together, these findings suggest that a transient period of enhanced antigenaemia during chronic SIV infection may serve to augment virus-specific immunity in some, but not all, macaques. These findings have relevance for induction of human immunodeficiency virus (HIV)-specific immune responses during prophylactic and therapeutic vaccination and for immunological evaluation of structured treatment interruptions in patients chronically infected with HIV-1.