Secondhand smoke exposure (SHSe) alters serum arachidonic acid (AA) metabolism in cystic fibrosis (CF). Serum lipidomics were measured by high-performance liquid chromatography-tandem mass spectrometry in a combined group of infants and children with CF. (A) SHSe was associated with a significant decrease in serum AA metabolites, specifically: prostaglandin D2 (PGD2), leukotriene C4, 8S-hydroxy-5Z, 9E, 11Z, 14Z-eicosatetraenoic acid (8(S)-HETE), 9S-hydroxy-5Z,7E,11Z,14Z-eicosatetraenoic acid (9(S)-HETE), 12(S)-hydroperoxy tetraenoic eicosatetraenoic acid (12(S)-HETE) and 14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid (14(15)-EET). (B) Decreased PGD2 concentrations were associated with increased hospitalisations (p=0.007, Wilcoxon rank-sum test) and (C) decreased weight z score (r=0.34, p=0.008). (D) PGD2 was not associated with FEV1 (r=0.19). Associations between other AA metabolite concentrations and hospitalisations, weight z score and FEV1 were not significant. PGD2 and other AA metabolite concentrations also did not correlate with height z score or oropharyngeal/sputum bacterial cultures (not shown). Correlations were performed using Pearson’s correlation coefficient.