The FEV(1) declines rapidly in alpha(1)-antitrypsin deficiency (alpha(1)-ATD) but less is known about other measures of disease severity and the factors, other than smoking, that are associated with progression of emphysema. The natural history of alpha(1)-ATD was studied prospectively in 43 patients with the PiZ phenotype and emphysema at a single center over 2 yr. The mean +/- SE change in FEV(1) was -67 +/- 14 ml/yr, accompanied by a reduction in transfer factor (mean change in diffusing capacity of the lung for CO [DL(CO)] -1.07 +/- 0.21 ml/min/mm Hg/yr; p < 0.001) and lung density in the upper zones as assessed by quantitative high-resolution computed tomography (HRCT) (mean change in voxel index 2.8 +/- 0.6%/yr; p < 0.001). The decline in FEV(1) related to baseline FEV(1) (r = -0.56, p < 0.001), bronchodilator reversibility (r = 0.52, p < 0.001), and (for patients with FEV(1) > 35% predicted) exacerbation frequency (r = -0.38, p = 0.02). There was also a decline in the St. George's Respiratory Questionnaire (SGRQ) Activity score (mean change -4.3 +/- 1.2 units/yr, p < 0.001) that correlated with FEV(1) decline (r = 0.45, p = 0.002). Progression of emphysema in alpha(1)-ATD is dependent on baseline physiology and exacerbation frequency and may be detected by several different measurements of which HRCT density mask analysis and DL(CO) appear most sensitive.