"Background COPD patients suffer from dysregulated and suppressed immune functionality, determined by their loss of degranulating capacity. Here we provide crucial information on the presence of degranulated MC in COPD airways and demonstrate their relationship to lung physiology and airway remodelling. Methods Small airway (SA) lung resections from non-smoking controls (NC), smokers with normal lung function (NLFS), small airway disease (SAD), mild-moderate COPD current smokers (CS), and ex-smokers (ES) were dual immuno-stained with mast cell tryptase and degranulation marker LAMP-1. Total MC, degranulating MC and non-MC were enumerated in SA epithelium and sub-epithelium, respectively, and in alveolar septa. Results In the SA wall, sub-epithelial areas, COPD-CS and -ES had significantly lower mast cells than NC (p<0.05), though considerably higher in SA epithelium (p<0.01). Degranulating non-mast cells were higher in SAD (p<0.05) than in COPD in SA sub-epithelium. In contrast, there were significant increases in total mast cells (degranulated and non-degranulated) and degranulated non-mast cells in the alveolar septum of COPD patients compared to NC (p<001). The lower numbers of mast cells in the sub-epithelium correlated with lower FEV1/FVC and FEF25-75%, higher smoking rates in COPD patients, and increased SA wall thickness and ECM. The increase in the alveolar in mast cells negatively correlated with FEF 25-75%. Conclusions This study is the first to assess the differential pattern of mast cells, degranulating mast and non-mast cell populations in the SA and alveoli of COPD patients. The spatial positioning of the mast cells within the airways showed variable correlations with lung function. Footnotes This manuscript has recently been accepted for publication in the ERJ Open Research . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article. Conflict of interest: Dr. Sohal has served on the Small Airway Advisory Board for Chiesi Australia and have received the honorarium, outside the submitted work. Conflict of interest: Dr Sohal reports travel support from Chiesi, GSK and AstraZeneca, outside the submitted work. Conflict of interest: Dr Sohal reports lecture honorarium from Chiesi outside the submitted work. Conflict of interest: Dr Sohal has received research grant from Lung Therapeutics outside the submitted work. Conflict of interest: Dr Eapen is currently employed as full-time employee in Mucpharm Pty Ltd. Conflict of interest: The work presented was not done as part of Dr Eapen's employment with Mucpharma Pty Ltd. Conflict of interest: All the other authors do not have any conflict of interest to declare."