Rationale: Increasing evidence supports a key role for the transcription factor nuclear factor-kappaB (NF-B) in the host response to pneumococcal infection. Control of NF-B activity is achieved through interactions with the IB family of inhibitors, encoded by the genes NFKBIA, NFKBIB and NFKBIE. Rare NFKBIA mutations cause immunodeficiency with severe bacterial infection, raising the possibility that common IB gene polymorphisms confer susceptibility to common bacterial disease. Objectives: To determine whether polymorphisms in NFKBIA, NFKBIB and NFKBIE associate with susceptibility to invasive pneumococcal disease (IPD) and thoracic empyema. Methods: We studied the frequencies of 62 single-nucleotide polymorphisms (SNPs)across NFKBIA, NFKBIB and NFKBIE in individuals with IPD and controls (n=1060). Significantly associated SNPs were then studied in a group of individuals with thoracic empyema and a second control group (n=632). Main results: Two SNPs in the NFKBIA promoter region were associated with protection from IPD in both the initial study group and the pneumococcal empyema subgroup. Significant protection from IPD was observed for carriage of mutant alleles at these two loci on combining the groups (SNP rs3138053, Mantel-Haenszel 2x2 ² =13.030, P=0.0003, odds ratio(OR)=0.60, 95% confidence interval (CI):0.45-0.79; rs2233406, Mantel-Haenszel 2x2 ² =18.927, P=0.00001, OR=0.55, 95% CI:0.42-0.72). An NFKBIE SNP associated with susceptibility to IPD but not pneumococcal empyema. None of the NFKBIB SNPs associated with IPD susceptibility. Conclusions: NFKBIA polymorphisms associate with susceptibility to IPD. Genetic variation in an inhibitor of NF-B therefore not only causes a very rare immunodeficiency state, but may also influence the development of common infectious disease.