The host immune factors that determine susceptibility to HIV-1 infection are poorly understood. We compared multiple immunologic parameters in three groups of HIV-1-seronegative men: 14 highly exposed (HR10), 7 previously reported possibly to have sustained transient infection (PTI), and a control group of 14 low risk blood bank donors (BB). Virus-specific cellular immune assays were performed for CD4+ T helper cell responses, CD8+ cytotoxic T lymphocyte activity, CD8+ cell chemokine release, and CD8+ cell-derived antiviral soluble factor activity. General immune parameters evaluated included CCR5 genotype and phenotype, interferon α production by PBMCs, leukocyte subset analysis, and detailed T lymphocyte phenotyping. Comparisons revealed no detectable group-specific differences in measures of virus-specific immunity. However, the HR10 group differed from the BB group in several general immune parameters, having higher absolute monocyte counts, higher absolute CD8+ T cell counts and percentages, lower naive and higher terminal effector CD8+ cells, and lower levels of CD28+CD8+ cells. These changes were not associated with seropositivity for other chronic viral infections. The PTI men appeared to have normal levels of monocytes and slightly elevated levels of CD8+ T cells (also with increased effector and decreased naive cells). Although we cannot entirely exclude the contribution of other chronic viral infections, these findings suggest that long-lived systemic cellular antiviral immunity as detected by our assays is not a common mechanism for resistance to infection, and that resistance may be multifactorial. General immune parameters reflected by CD8+ T cell levels and activation, and monocyte concentrations may affect the risk of infection with HIV-1, and/or serve as markers of exposure.