ABSTRACT The effects of the challenge dose and major histocompatibility complex (MHC) class IB alleles were analyzed in 112 Mauritian cynomolgus monkeys vaccinated ( n = 67) or not vaccinated ( n = 45) with Tat and challenged with simian/human immunodeficiency virus (SHIV) 89.6P _cy243. In the controls, the challenge dose (10 to 20 50% monkey infectious doses [MID ₅₀ ]) or MHC did not affect susceptibility to infection, peak viral load, or acute CD4 T-cell loss, whereas in the chronic phase of infection, the H1 haplotype correlated with a high viral load ( P = 0.0280) and CD4 loss ( P = 0.0343). Vaccination reduced the rate of infection acquisition at 10 MID ₅₀ ( P < 0.0001), and contained acute CD4 loss at 15 MID ₅₀ ( P = 0.0099). Haplotypes H2 and H6 were correlated with increased susceptibility ( P = 0.0199) and resistance ( P = 0.0087) to infection, respectively. Vaccination also contained CD4 depletion ( P = 0.0391) during chronic infection, independently of the challenge dose or haplotype.