We concurrently evaluated host- and organism-related factors in determining the outcomes of 160 invasive pneumococcal diseases episodes in 158 Taiwanese children during 2001 and 2006. Most (138/160, 86.2%) episodes occurred at age less than 60 months, and an underlying condition was present in 35 (22.2%) cases. Common disease syndromes included complicated pneumonia (29.4%), uncomplicated pneumonia (29.4%), occult bacteremia (17.5%), and meningitis (14.4%). Mortality (13/160, 8.1%) was associated with age less than 24 months, underlying conditions, meningitis, cytopenia, intensive care, and penicillin MIC >or=2 microg/mL in univariate analysis. Pneumococcal serotypes, genotypes, origin of infections, and discordant therapy did not influence the outcome. Multivariate analysis determined the presence of underlying conditions (adjusted odds ratio [OR], 30.5; 95% confidence interval [CI], 4.8-193.1) and penicillin MIC >or=2 microg/mL (adjusted OR, 8.1; 95% CI, 1.4-47.3), which are the independent predictors for fatality. This finding highlighted the importance of immunization of disadvantaged children, targeting drug-resistant pneumococci.