The 23-valent-polysaccharide pneumococcal vaccine (PPV23) is currently recommended for patients at high risk for invasive disease from Streptococcus pneumoniae. It is also frequently used in the evaluation of patients with suspected immunodeficiency. Reports of systemic adverse reactions are rare. Our objective is to describe a patient with an apparent systemic reaction to PPV23 and review our hospital's 2-year experience with pneumococcal vaccine. Chart review of 173 patients given PPV23 between January 1, 2004 and December 31, 2005 revealed five who had significant adverse reactions, including local cellulitis, fever, and vomiting. Variables considered included age at immunization, indication for PPV23, and prior pneumococcal vaccines. The mean age of all patients given PPV23 during the defined time period was 8.6 years, and the most common indication for vaccination was recurrent infection. Of those patients who had adverse reactions, the mean age was 6.5 years. The time from prior pneumococcal vaccination was a mean of 20 months in children who did not have an adverse reaction. None of the patients who had an adverse reaction had documentation of receiving PPV23 before. Local reactions to PPV23 occur in approximately 50% of recipients, and revaccination of immunocompetent individuals increases the risk for local reaction. Systemic reactions are less common and only occur in approximately 1% of recipients. Our patient had no identifiable risk factors for development of an adverse reaction. Additional studies are indicated to determine whether there are identifiable risk factors for the development of adverse reactions to PPV23.