Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor I?B?, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how I?B? might regulate inflammatory responses to pneumococcal infection. We first demonstrate that I?B? is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced I?B? in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, I?B? knockdown reduced the expression of IL-6 and GMCSF. Furthermore, I?B? overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced I?B?. While inhibition of TLR1/TLR2 blocked D39 induced I?B? expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NF?B suppressed D39 induced I?B?. Overall, our data demonstrates that I?B? regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF.