In order to determine whether combination antibiotic therapy decreases mortality after severe pneumococcal infection, a retrospective study of a cohort of 1,840 adult patients with severe sepsis or septic shock enrolled in two multicenter clinical trials between 1994 and 1999 was conducted. Among 107 patients with monobacterial pneumococcal sepsis, the case-fatality rate was 20% (five of 25) for patients who received antibiotic monotherapy compared with 19.5% (16 of 82) for patients who received combination therapy (adjusted hazard ratio, 1.1; 95% CI, 0.4-3.1). Similarly, monotherapy did not increase the risk of death (adjusted hazard ratio, 1.0; 95% CI, 0.2-4.8) among bacteremic patients (n=75). However, the latter analysis may have been underpowered (power, 58%) to detect a difference in mortality. Overall, in contrast to recently published reports, these results suggest that combination antibiotic therapy does not decrease mortality after severe pneumococcal sepsis.