Gram-positive bacteria, which lack lipopolysaccharide (LPS), produce a septic-shock-like condition, accompanied by release of pro-inflammatory cytokines. Various components of the bacteria may be responsible for this. We stimulated a whole blood system with heat-inactivated Streptococcus pneumoniae serotype 14 (S14) bacteria, with pneumococcal S14 capsular polysaccharide (PPS S14) and with PPS S14 coated on to latex beads, to compare interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFalpha) production over a six hour period, to ascertain the contribution of PPS to the inflammatory response. This was compared with the response to LPS. After sonication of the bacteria, their PPS content was estimated by an enzyme-linked immunoabsorbent assay, to compare this with the concentration of free PPS needed to generate cytokine release. The whole bacteria elicited a much larger cytokine response than the equivalent amount of PPS alone, whereas the PPS-coated beads gave minimal response. The different cytokine responses to PPS and LPS suggest that there are differences in the receptors and/or signalling pathways for Gram-negative and Gram-positive bacteria. We conclude that the estimated amount of PPS in the bacteria is not enough to account for the large cytokine response we observed. Since PPS could not be shown to contribute significantly to cytokine induction, specific antibodies to PPS would not play any significant role in combating cytokine release associated with pneumococcal infection and possible septic shock. This needs to be considered in production of future vaccines.