INTRODUCTION: Progressive loss of lung function is recognized in COPD, however, remains heterogenous between individuals. No study concurrently evaluates mucus properties, the lung microbiome and lung function decline in COPD. METHODS: Prospective longitudinal assessment (up to 11 years) of n=58 individuals from the London COPD cohort were assessed using ?paired? sputum (total 116 specimens) and categorised into ?Fast decliners? (>50 mL/year FEV₁ loss; n= 30) and ?control-COPD? (physiological airflow decline; n=28). Lung microbiomes were assessed by shotgun metagenomics and corresponding mucus profiles evaluated for biochemical and biophysical properties at both time points. RESULTS:  Increased MUC5AC / MUC5B concentrations (p<0.001) and mucus elasticity (p<0.001) associate with ?Fast decliners?. Lung microbiomes demonstrate no compositional difference between the initial and follow-up timepoints, however, longitudinal change is observed between ?Fast decliners? and ?Control-COPD? characterized by increases in Haemophilus, Pseudomonas, and Moraxella (PPMs) and loss of Streptococcus, Prevotella, and Rothia. Strong correlations between PPMs and mucus biochemical profile are evident, while upper airway commensals negatively correlate with mucus biochemistry. No association between microbes and mucus biophysical profile were detected. CONCLUSION: Key relationships between airflow decline, biochemical and biophysical components of mucus and the lung microbiome exist in COPD, features providing novel insight to inform therapeutic development targeting the mucus-microbiome interface. FUNDING: LKCMedicine?ICL Fellowship (#020458-00001) (O.W.M) and Singapore MOH NMRC under its Clinician Scientist Award (MOH-000710) (S.H.C).