In the present study, we sought to define the importance of serum IgA (sIgA)-mediated immunity in HIV-2 infection. Serum samples from a total of 29 HIV-2-infected patients from Guinea-Bissau (n = 20) and Portugal (n = 9) were studied. Samples from seronegative individuals were used as controls. Antibody reactivity to native and recombinant envelope glycoproteins as well as peptides representing various regions of the envelope glycoproteins was investigated. Furthermore, the capacity of purified IgA to neutralize the HIV-2(SBL6669) strain was tested. All serum samples showed IgA reactivity against whole HIV-2 antigen. Twenty-eight out of 29 IgA samples (96%) reacted with native HIV-2 gp125, 26/29 (90%) with recombinant gp105, and 29/29 (100%) with recombinant gp36. When using peptides, the most prominent IgA reactivity was seen against the peptide representing aa 644-658 of the transmembranous protein gp36, to which 72% of the sera reacted. Purified sIgA antibodies showed neutralizing effects against HIV-2(SBL6669) in 17/29 cases (59%). This work describes the HIV-2-specific sIgA antigenic response. Moreover, our findings show, for the first time, that sIgA may play a role in the in vitro neutralization of HIV-2.