OBJECTIVE: To determine whether immunocompetent elderly patients with low serum vitamin B12 levels have impaired serum antibody responses to the 23-polyvalent pneumococcal polysaccharide vaccine. DESIGN: Controlled, prospective cohort study. MEASUREMENTS: 15 patients with low serum vitamin B12 levels and 15 age- and diagnosis-matched patients with normal levels were vaccinated. Serum antibody titers to 12 pneumococcal serotypes were measured by radioimmunoassay before and 4 weeks after vaccination. RESULTS: The difference between the geometric mean of the vaccine antibody titers before and after vaccination for all 12 serotypes was lower (P = 0.005) in the patients with low vitamin B12 levels than in the patients with normal levels. When mean corpuscular volume and age were controlled for, vitamin B12 remained an independent predictor of antibody response (P = 0.005). Erythrocyte mean corpuscular volume was also an independent predictor of the increase in titer (P = 0.03). CONCLUSIONS: Patients with low vitamin B12 levels had impaired antibody responses to pneumococcal vaccine. Further study is necessary to determine whether treatment with vitamin B12 can enhance specific immunoglobulin synthesis and improve the clinical efficacy of the pneumococcal vaccine in patients with low vitamin B12 levels.