We have undertaken this retrospective study to determine factors associated with in-hospital mortality and morbidity in 80 adult patients with severe Streptococcus pneumoniae meningitis. Clinical characteristics at admission of patients infected with susceptible (n = 54) and nonsusceptible (n = 17) strains to penicillin G were similar: age: 51 +/- 19 versus 58 +/- 15 yr (p = 0.16); Simplified Acute Severity Score (SAPS II): 39 +/- 14 versus 41 +/- 11 (p = 0.68); and Glasgow Coma Score: 8 +/- 3 versus 9.5 +/- 3 (p = 0.21), respectively. In-hospital mortality was 25% (20/80), with one death among the 17 patients (6%) infected with a nonsusceptible strain (p = 0.03). High-dose dexamethasone was used in 22 cases. By multivariate analysis, three factors were independently associated with death: platelet count < 100 G/L (adjusted odds ratio [aOR] = 32.7; 95% CI = 3.2 to 332.5; p = 0.0032), arterial pH > 7.47 (aOR = 33.1; 95% CI = 3.4 to 319.7; p = 0.0025), and mechanical ventilation (aOR = 48.8; 95% CI = 2.6 to 901.5; p = 0.009). When adjusting for the identified prognostic factors, corticosteroids significantly reduced the risk of death (aOR = 0.069; 95% CI = 0.005 to 0.9; p = 0.048). Only SAPS II was predictive of adverse outcome (death or neurologic deficit). We conclude that in intubated patients with S. pneumoniae meningitis, hyperventilation should be used with caution. Nonsusceptibility to penicillin G is not associated with a worse outcome. High-dose corticosteroids may be beneficial in the most severely ill patients.