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Abstract: Human primary immunodeficiencies affecting Toll-like receptor (TLR) signalling reveal a non-redundant role for TLR function in defense against pneumococcal infection. To determine the clinical relevance of TLR abnormalities, we studied a population predicted to be enriched for TLR defects—healthy children who had developed invasive pneumococcal infection in the absence of classic risk factors for infection. We describe the development and optimization of a peripheral blood TLR assay. By testing 38 healthy control neonates, children and adults we demonstrated that TLR function was stable over the first six decades of life. We tested 50 children with a history of invasive pneumococcal infection and although TLR defects were predicted to be over-represented in this population, we did not identify any TLR abnormalities. Although TLR signalling defects are associated with greatly enhanced susceptibility to invasive pneumococcal infection, our results suggest that routine clinical screening for TLR defects in healthy children who develop invasive pneumococcal infection is not justified. [Copyright &y& Elsevier]