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Invasive pneumococcal disease is a significant cause of morbidity and mortality in the United States. Despite availability of an effective vaccine, many patients refuse vaccination. To investigate patient characteristics and features of the patient–provider relationship associated with pneumococcal vaccine refusal. Case–control study using chart review. Five hundred adults from the medical clinics of a 1,000-bed inner-city teaching hospital. Independent risk factors for pneumococcal vaccine refusal included patient–provider gender discordance (odds ratio (OR)=2.09, 95% confidence interval (CI) 1.07 to 4.09); a visit to a not-usual provider at the time of vaccine offering (OR=2.26, 95% CI 1.13 to 4.49); never having received influenza vaccination (OR=7.44, 95% CI 3.76 to 14.76); prior pneumococcal vaccine refusals (OR=3.45, 95% CI 1.60 to 7.43); and a history of ever having refused health maintenance tests (OR=2.86, 95% CI 1.40 to 5.84). We have identified both patient factors and factors related to the patient–provider relationship that are risk factors for pneumococcal vaccine refusal. By identifying patients at risk for pneumococcal vaccine refusal, efforts to increase vaccination rates can be better targeted. [ABSTRACT FROM AUTHOR]