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Early diagnosis and disease phenotyping in COPD are currently limited by the use of spirometry, which may remain normal despite significant small-airways disease and which may not fully capture a patient’s underlying pathophysiology. In this study we explored the use of a new non-invasive technique that assesses gas-exchange inhomogeneity in patients with COPD of varying disease severity (according to GOLD Stage), compared with age-matched healthy controls. The technique, which combines highly accurate measurement of respiratory gas exchange using a bespoke molecular flow sensor and a mechanistic mathematical model of the lung, provides new indices of lung function: the parameters σCL, σCd, and σVD represent the standard deviations of distributions for alveolar compliance, anatomical deadspace and vascular conductance relative to lung volume, respectively. It also provides parameter estimates for total anatomical deadspace and functional residual capacity (FRC). We demonstrate that these parameters are robust and sensitive, and that they can distinguish between healthy individuals and those with mild-moderate COPD (stage 1–2), as well as distinguish between mild-moderate COPD (stage 1–2) and more severe (stage 3–4) COPD. In particular, σCL, a measure of unevenness in lung inflation/deflation, could represent a more sensitive non-invasive marker of early or mild COPD. In addition, by providing a multi-dimensional assessment of lung physiology, this technique may also give insight into the underlying pathophysiological phenotype for individual patients. These preliminary results warrant further investigation in larger clinical research studies, including interventional trials.