Severe pneumonia and meningitis caused by Streptococcus pneumoniae have been persistently associated with high mortality rates, despite advances in antimicrobial therapy and the development of vaccines. Resistance to penicillin and other antimicrobial agents is increasing and spreading worldwide. Even though risk factors for development of antimicrobial resistance have been identified, their influence on mortality has not been clarified. With regard to virulence, differences among serotypes have been determined, but their impact on mortality is unknown. The aim of this study was to determine the risk factors associated with mortality in children with invasive pneumococcal disease. Clinical records for 245 children under 5 years of age with invasive disease due to S.pneumoniae were reviewed. Children were diagnosed between 1994 and 1996 in Colombia, during the study of S.pneumoniae capsular types conducted by the Pan American Health Organization's Regional System for Vaccines. Of the 245 patients whose charts were examined, 29 (11%) died. No significant differences in age, gender, underlying disease, nor antimicrobial treatment concordance were found. Variables associated with mortality in the univariate analysis were a diagnosis of meningitis; antimicrobial resistance to penicillin, trimethoprim-sulfamethoxazole (TMS), or erythromycin; multiresistance, and serotypes 6, 23F, 7F, 8, and 35B. In the logistic regression, serotypes 7F (OR = 7.13; P = 0.04) and 8 (OR = 13.8; P = 0.07), polipnea (OR = 2.74; P = 0.03), meningitis (OR = 5.02; P = 0.0001) and TMS resistance (OR = 2.62; P = 0.02) continued to be associated with mortality. In patients with pneumonia, serotype was the factor most consistently associated with mortality; in meningitis patients, it was antimicrobial resistance. Differences in mortality according to serotype must be taken into account in developing a vaccine if a substantial impact on pneumococcal disease morbidity and mortality is to be achieved.