To determine whether defects in mucosal immunity were associated with invasive disease caused by a mucosal pathogen, Streptococcus pneumoniae, levels of salivary immunoglobulins and nonspecific immune factors were compared in subjects with human immunodeficiency virus type 1 (HIV-1) infection and in HIV-1-seronegative subjects with and without pneumococcal bacteremia. The IgA2 subclass may be of particular importance because S. pneumoniae produces IgA1 protease, which cleaves IgA1 but not IgA2. Levels (37-56 μg/mL) and proportions (11%-17%) of IgA2 were similar among groups. Serotype-specific capsular salivary 19A was present in a minority of patients with acute bacteremia. Levels of lactoferrin were increased with bacteremia. Neither selective mucosal IgA2 deficiency nor impaired nonspecific upper respiratory mucosal responses were associated with invasive pneumococcal disease during HIV-1 infection; thus, other defects in mucosal cellular responses and systemic immunity may predispose HIV-1-infected patients to invasive pneumococcal disease.