Rationale: The majority of previous studies investigating asthma genetics have focussed on cohorts with stable disease and have not defined mechanisms important during acute asthma. CD14 and CC16 each play a key role in biologically important inflammatory pathways and the gene of each has a functional promoter region polymorphism. Objectives: This study was designed to determine the influence of these polymorphisms on plasma levels of their products and clinical disease during acute asthma. We hypothesised that genotype-related differences in CD14 and CC16 production would be more marked during acute asthma and related to disease severity. Methods: We studied 148 children on presentation with acute asthma and again in convalescence. CD14 C-159T and CC16 A38G genotypes were determined and plasma sCD14 and CC16 levels measured at both time points. Measurements and Main Results: During acute asthma, plasma sCD14 levels were higher for the whole group (p=0.003), but increases were only in those with CD14 -159TT (p=0.003) and -159CT (p=0.004), not -159CC. Plasma CC16 levels were also elevated acutely for the whole group (p=0.013), but only in those with CC16 38GG (p=0.043) and 38AG (p=0.014), not CC16 38AA. CD14 -159CC and CC16 38AA subjects were more likely to have moderate or severe acute asthma. Conclusions: Plasma levels of sCD14 and CC16 were higher during acute asthma in children. Those with CD14 -159CC and CC16 38AA had no change in sCD14 and CC16 levels and more severe asthma.