Abnormalities in the phase III nitrogen slope in a group of healthy smokers with otherwise normal lung function have been previously reported for SBWvc, but only when the smokers forcibly exhaled to Rv immediately before performing the SBWvc manoeuvre . The proposed mechanism for this effect of smoking was that the rapid forced exhalation just preceding the SBWvc manoeuvre delayed regional emptying in peripheral regions distal to small airway inflammation and narrowing in the lungs of smokers. This reveals the presence of this disease process by transiently altering the spatial distribution ventilation by increasing specific ventilation in regions distal to the airway narrowing. In the present study, SBWvc manoeuvres were preceded by a deep breath, consisting of slow exhalation to Rv, so that we would not have expected changes in ventilation inhomogeneity in otherwise healthy smokers due to the former mechanism ; indeed, Sn and Emix for SBWvc manoeuvres in smokers were normal. However, Di was unexpectedly increased and did not correlate with changes in Sn in smokers suggesting that an additional factor, other than alterations in ventilation inhomogeneity, was involved. The increase in Di due to smoking for these SBWvc manoeuvres may have been due to reductions in gas diffusion in macroscopic regions of emphysema that remained ventilated, but that emptied preferentially early in expiration. This appeared unlikely because macroscopic emphysema was thought to be ventilated poorly and largely by collateral channels . Alternatively, and more likely, the effect of smoking on Di for these SBWvc manoeuvres may have been due to the same mechanism proposed for SBWSM manoeuvres as described above. That is, centrilobular emphysema could have caused proximal destruction of terminal respiratory units, resulting in an exaggeration of the serial gradients in diffusion from the proximal (reduced diffusion) to the distal (increased diffusion) segments of terminal respiratory units.