Background: Asthma has been reported to be associated with an increased risk of invasive pneumococcal disease (IPD). Objective: We compared serotype-specific antibody responses with pneumococcal polysaccharide antigens of individuals with and without asthma. Methods: A cross-sectional study was conducted for 16 subjects with asthma and 14 subjects without asthma from the community of Rochester, MN. Asthma was determined by predetermined criteria based on comprehensive medical record reviews. Serotype-specific antibody to 23 pneumococcal polysaccharide antigens was measured by enzyme-linked immunosorbent assay, and seropositivity was considered ≥ 1.3 μg/mL. Interferon-γ (IFN-γ) and interleukin-5 (IL-5) were measured from peripheral blood mononuclear cells cultured with house dust mites and staphylococcal enterotoxin B. Results: Of the 30 subjects, 16 (53%) were male, 21 (70%) were white, and the median age was 26 years. The median numbers of positive serotype-specific antibodies for asthmatics and nonasthmatics were 8.5 and 15.5, respectively (P = 0.034). There was an inverse relationship between the ratio of log-transformed IL-5/IFN-γ and the number of positive serotype-specific antibodies (r = -0.36; P = 0.052). As potential covariates and confounders, a history of pneumococcal vaccination (P = 0.84), having a high-risk condition for IPD (P = 0.68), and taking asthma medications, including inhaled/systemic corticosteroids (P = 0.79), were not associated with the number of positive serotype-specific antibodies. Conclusion: Asthmatics had significantly lower serotype-specific pneumococcal antibody levels than nonasthmatics. House dust mite-induced T-helper 2 (Th2) cytokine immune profile may be related to the association. This may account for an increased risk of IPD in asthmatics and deserves further investigation.© Postgraduate Medicine.