The effect of IgA from human immunodeficiency virus type 1 (HIV-1)-infected patients on infection of primary human blood monocytes with the monocyte-tropic strain HIV-1Bal was evaluated in vitro. Preincubation of HIV-1Bal with purified serum IgA from 6 of 14 patients but from none of 5 seronegative subjects caused a > 50% increase in reverse transcriptase activity. This increase was inhibited by preincubation of monocytes with nonimmune IgA, suggesting a role for Fc alpha receptors. Results were independent of CD4 T cell number and clinical stage. The IgA-mediated enhancement extended to more biologically relevant human mononuclear cells isolated from the intestinal lamina propria. The ability of serum IgA to enhance HIV-1 infection may be relevant to infection of both circulating monocytes and mucosal macrophages. These studies suggest the need to characterize the complex contribution of IgA and the mucosal immune system in promoting and preventing primary HIV-1 infection.