BACKGROUND: Measuring antibody responses to 23-valent pneumococcal polysaccharide vaccines (PPV) is crucial to evaluation of humoral immune function. However, data are limited comparing responses in immunodeficient subjects. OBJECTIVE: A case-controlled study comparing changes in PPV antibody titer in immunocompetent and immunodeficient children was performed to validate current guidelines. METHODS: A cohort of 95 immunocompetent children and 22 HIV-infected children, ages 2 to 15 years, was vaccinated with PPV, and before and after vaccination, IgG titers against capsular polysaccharides for 12 pneumococcal serotypes were measured. Results were used to calculate the receiver operator characteristic curve, sensitivity, and specificity of various interpretation criteria for their accuracy in detecting suboptimal responders. RESULTS: Immunodeficient subjects had lower CD4%, antidiphtheria, antitetanus titers, and mean post-PPV titers (2.5 +/- 1.7 vs 4.5 +/- 2.1 mug/mL; P < .001) compared with immunocompetent subjects. The interpretation, using individual post-PPV titer of > or =4-fold increase over prevaccination as a positive response, yielded the highest accuracy as measured by area under the curve value (receiver operator characteristic curve = .755). For this criterion, the numbers of serotypes with positive responses of < or =5 of 12 serotypes measured yielded 72.7% sensitivity and 56.8% specificity in detecting antibody-deficient subjects. CONCLUSION: Current guidelines using > or =4-fold increase in post-PPV titers has sufficient sensitivity and specificity to identify antibody deficiency. The minimal positive responses should be at least 50% of serotypes tested. CLINICAL IMPLICATIONS: Measurement of PPV antibody response based on the current guidelines accurately identify children with humoral immunodeficiency.