Systemic infection with Streptococcus pneumoniae was investigated in male and female mice in models of invasive pneumonia and sepsis. Male mice were found to be more susceptible to infection, exhibiting greater weight loss, marked decrease in body temperature, and a significantly higher mortality rate compared with female mice. For pneumonia, there were significant differences in survival rates. Female mice cleared their lung infections over time, whereas male mice, compared with female mice, had significantly increased numbers of colony-forming units in early stages of infection accompanied by higher levels of neutrophil recruitment in the first 24 hours after infection. Importantly, there were significant increases in proinflammatory cytokine levels during both sepsis and pneumonia in male compared with female mice. These cytokines were indicative of T-helper 1–type responses. The data presented here describe surprising differences in survival rates, neutrophil recruitment, and proinflammatory cytokine levels, indicating a sex-based difference in susceptibility to respiratory and systemic pneumococcal disease.