Objective: Asthma poses an increased risk for serious pneumococcal disease, but little is known about the influence of asthma status on the 23-valent serotype-specific pneumococcal antibody response. We examined differences in antibody titers between pre- and post-vaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV-23) in relation to asthma status. Methods: Asthma status was retrospectively ascertained by the Predetermined Asthma Criteria in an existing vaccine cohort through comprehensive medical record review. Twenty-three serotype-specific pneumococcal antibody titers measured at baseline and 4-6 weeks post-vaccination were analyzed. Vaccine responses to PPSV-23 were calculated from pre- to post-vaccine titers for each of the serotypes. Results: Of the 64 eligible and enrolled subjects, 18 (28%) had asthma. Controls (i.e., subjects without asthma) demonstrated a statistically significant fold change response compared to their baseline for all serotypes, while those with asthma did not mount a significant response to serotypes 7F, 22F, and 23F. The overall vaccine response as measured by fold change over baseline was lower in subjects with asthma than controls. Conclusions: Poorer humoral immune responses to PPSV-23 as measured by fold change were more likely to be observed in subjects with asthma compared to controls. We recommend the consideration of asthma status when interpreting vaccine response for immune competence workup through larger studies. Further studies are warranted to replicate these findings.