Bacteremic pneumonia with some pneumococcal capsular serotypes, including serotype 3 (ST3), has been associated with a higher risk of death, whereas others, such as ST8, are associated with a lower risk. To provide a molecular basis for understanding such differences, we used oligo cDNA microarrays to analyze and compare the gene expression profiles of the lungs of Balb/c mice infected intranasally with either ST3, strain A66.1, or ST8, strain ATCC 6308 (6308). Compared to uninfected controls, infection with either A66.1 or 6308 led to inoculum-dependent expression of IFN-γ inducible CXC chemokines among other pro-inflammatory genes. To investigate the role that IFN-γ inducible chemokines CXCL9, CXCL10 and CXCL11 play in A66.1- and 6308-induced pneumonia, we examined the effect of the absence of their common receptor, CXCR3, on intranasal infection in CXCR3 −/− (Balb/c) mice. Compared to wild type (WT) mice, virulence of A66.1 but not 6308 was attenuated in CXCR3 −/− mice. A66.1-infected CXCR3 −/− mice had fewer lung neutrophils and more alveolar macrophages 48h after infection and fewer blood CFU 72h after infection. Histopathological examination of lung sections revealed less inflammation among A66.1-infected CXCR3 −/− than WT mice. The reduced virulence of A66.1 in CXCR3 −/− mice suggests that inhibition of the functional activity of IFN-γ inducible chemokines modulates the host response to A66.1, in turn suggesting a novel approach to improve vaccine-mediated protection against ST3 pneumonia.