Candida albicans mannan is the major cell wall antigen that elicits antibodies considered to be of little diagnostic value. It comprises epitopes corresponding to sequences of alpha- and beta-1,2-linked mannose residues. Both types of oligomannosidic epitopes may also be present on the glycosidic portions of other C. albicans molecules, i.e., mannoproteins (MP) (either structural or enzymatic) and glycolipids. The human humoral responses against beta-1,2- and alpha-linked oligomannosides were investigated by C. albicans Western blotting by considering the elective distribution of beta-1,2-oligomannosidic epitopes over a 14- to 18-kDa phospholipomannan (PLM) and the presence of alpha-mannosidic epitopes over heavily glycosylated MP. Western blotting of 51 control sera confirmed the presence of antibodies against C. albicans as a commensal member of the indigenous microflora; an immunoglobulin G (IgG) reactivity linked to enzyme-linked immunosorbent assay mannan signals was found for both PLM (beta-1,2-Man residues) and MP (alpha-Man residues). Despite strong reactivities against mannan and MP, IgG from 21 hospitalized patients with mycological evidence of deep-tissue invasion by C. albicans very significantly failed to react or reacted only faintly with PLM. This downregulation of anti-beta-1,2-oligomannosidic epitopes, associated with tissue invasion by C. albicans, was confirmed in 3 of 4 AIDS patients with extended oroesophageal candidosis. The application of a dissociation procedure proved that the absence of PLM reactivity was not due to the presence of immune complexes. These data provide the first evidence for a qualitative modification of the human antimannan antibody response associated with the C. albicans commensal-pathogenic transition.