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However, effects of ETI on downstream consequences of CFTR dysfunction,<jats:italic>i.e.<\/jats:italic>abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two<jats:italic>F508del<\/jats:italic>alleles aged \u226512\u2005years throughout the first 12\u2005months of therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12\u2005months after initiation of ETI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In total, 79 patients with CF and at least one<jats:italic>F508del<\/jats:italic>allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12\u2005months after initiation (all p&lt;0.01). Furthermore, ETI decreased the relative abundance of<jats:italic>Pseudomonas aeruginosa<\/jats:italic>in CF sputum at 3\u2005months and increased the microbiome \u03b1-diversity at all time points<jats:italic>.<\/jats:italic>In addition, ETI reduced interleukin-8 at 3\u2005months (p&lt;0.05) and free neutrophil elastase activity at all time points (all p&lt;0.001), and shifted the CF sputum proteome towards healthy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one<jats:italic>F508del<\/jats:italic>allele over the first 12\u2005months of therapy; however, levels close to healthy were not 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