Whether highly active antiretroviral therapy (HAART) impacts responses to 23-valent pneumococcal polysaccharide vaccine (PV) is not known. Immunoglobulin G (IgG) levels for 6 capsular polysaccharides in human immunodeficiency virus (HIV)-infected patients who had received > or =6 months of HAART were measured either after their first dose of PV (n=46) or after revaccination (n=41); control subjects had never received HAART and had received the first dose of PV (n=38). There were no significant differences in pre- or postvaccination IgG levels among these groups but for 1 capsular polysaccharide. The 3 groups had significant postvaccination increases in IgG levels to all capsular polysaccharides. The control group had a greater number of 2-fold responses than did the combined HAART groups (P<.05). Patients with a CD4 cell count of > or =200 cells/mm3 had a greater number of 2-fold responses than did those with a CD4 cell count of <200 cells/mm3 (P<.05). For revaccinated patients, postvaccination IgG levels were correlated with the CD4 cell count at the initial vaccination. The immunogenicity of PV among patients receiving long-term HAART is modest. It seems best to immunize HIV-infected patients early in the course of disease.