The slope of phase III of the single-breath nitrogen wash-out test (sbN2-test) measures ventilation inhomogeneity and, in smokers, is strongly associated with small airways pathology. The present authors aimed to study ventilation inhomogeneity in emphysema related to type Z alpha1-antitrypsin (AAT) and to assess its relationship with indices of parenchymal damage and airways obstruction. A total of 18 subjects, consisting of ex-smokers with type Z AAT and emphysema (confirmed by computed tomography scan), were studied in a cross-sectional design. Post-bronchodilation flow-volume curves and gas transfer parameters were measured; sbN2-test curves were obtained and the slope of phase III was determined. The mean value of the slope (4.6+/-1.3% N2 x L(-1)) was higher than reference values +2sd; it was significantly correlated with the transfer factor of the lung for carbon monoxide (R = -0.75) and the transfer coefficient of the lung for carbon monoxide (R = -0.58), but not with airways obstruction. There was no correlation between phase III slope values and cumulative smoking. In patients with type Z alpha1-antitrypsin emphysema, the increased ventilation inhomogeneity predominantly reflects parenchymal abnormalities, demonstrating that measurement of airways obstruction is not sufficient to characterise the disease. Determination of the sensitivity of the single-breath nitrogen wash-out test slope in detecting disease progression may give complementary information to spirometry.