Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and a major cause of morbidity and mortality throughout the world. It has been a major research priority to identify gene polymorphisms responsible for/associated with susceptibility and severity of S. pneumoniae infection to gain a better understanding of host genetic variants and their influence and clinical relevance to pneumococcal infections. In the present study, polymorphisms in several candidate genes, including TLR2-Arg/Gln753, TLR4-Asp/Gly299, TLR4-Thr/Ile399, CD14-159C/T and FcgammaRIIA-R/H131, were examined in 85 children with pneumococcal sepsis as an invasive pneumococcal disease and 409 healthy blood donors as controls. The prevalence of the TLR4-299/399 polymorphisms was significantly lower in the patient population than in controls (4 vs 11%; P<0.05; odds ratio (OR) 0.3; 95% confidence interval (CI) 0.1-1), while the prevalence of the CD14-159CC and FcgammaRIIA-R/R131 genotypes was significantly higher (35 vs 25%; P<0.05; OR 1.7; 95% CI 1-2.8 and 39 vs 21%; P<0.001; OR 2.5; 95% CI 1.4-4, respectively). Further, only 35% of patients carried either low-risk genotypes or protective genotypes in contrast to 61% of controls (P<0.0001; OR 2.8; 95% CI 1.7-4.6). We conclude that genetic variability in the TLR4, CD14 and FcgammaRIIA genes is associated with an increased risk of developing invasive disease in patients who are infected with S. pneumoniae.