The absolute number of CD4⁺ lymphocytes in blood is prognostic for disease progression, yet the cell surface density of CD4 receptors or chemokine receptors on a single cell has not previously been found to be predictive of human immunodeficiency virus (HIV) infectivity outcome. It has recently been shown that human leukocyte elastase (HLE) and its ligand ₁ proteinase inhibitor (₁PI; ₁ antitrypsin) act as HIV fusion cofactors. The present study shows that decreased HIV infectivity is significantly correlated with decreased cell surface density of HLE but not with decreased CD4 nor chemokine receptors. In vitro HIV infectivity outcome in this study was predicted by the surface density of HLE on mononuclear phagocytes but not on lymphocytes. The set point HLE surface density was in part determined by ₁PI. Decreased circulating ₁PI was correlated with increased cell surface HLE and with increased HIV infectivity. The correlation of HIV infectivity outcome with surface HLE and circulating ₁PI supports the utility of these HIV cofactors in diagnostic analysis and therapeutic intervention.