Plasma stromal cell-derived factor (SDF)-1 levels, SDF1-3'A polymorphism, and CXCR4(+) T lymphocytes in relation to resistance to human immunodeficiency virus (HIV)-1 infection and its progression were investigated in a study of HIV-positive patients, exposed but uninfected (EU) subjects, and healthy control subjects, all lacking CCR5 Delta 32 homozygosity. SDF1-3'A homozygosity was associated with low plasma SDF-1 levels in uninfected persons and was not related to long-term nonprogression. HIV-1 infection involved increased plasma SDF-1 levels, which were not attributable to any kind of chronic viral infection, because all EU hemophiliacs were hepatitis C virus-positive but had normal SDF-1 levels. High plasma SDF-1 levels and low CXCR4 expression on T lymphocytes was associated with long-term nonprogression, whereas in advancing disease expression of CXCR4 increased, accompanied by a decrease in plasma SDF-1 during the more advanced stages of HIV-1 infection. EU subjects with sexual exposure to HIV-1, but not EU hemophiliacs, showed an underpresentation of SDF1-3'A allele frequency, which was coupled with high plasma SDF-1 levels and low CXCR4 expression.