Subjects ⩾ 18 yr of age with serum α₁-antitrypsin ( α₁-AT) levels ⩽ 11 μ M or a ZZ genotype were followed for 3.5 to 7 yr with spirometry measurements every 6 to 12 mo as part of a National Heart, Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1-Antitrypsin. Among all 1,129 enrollees, 5-yr mortality was 19% (95% CI: 16 to 21%). In multivariate analyses of 1,048 subjects who had been contacted ⩾ 6 mo after enrolling, age and baseline FEV₁% predicted were significant predictors of mortality. Results also showed that those subjects receiving augmentation therapy had decreased mortality (risk ratio [RR] = 0.64, 95% CI: 0.43 to 0.94, p = 0.02) as compared with those not receiving therapy. Among 927 subjects with two or more FEV₁ measurements ⩾ 1 yr apart, the mean FEV₁ decline was 54 ml/yr, with more rapid decline in males, those aged 30 to 44 yr, current smokers, those with FEV₁ 35 to 79% predicted, and those who ever had a bronchodilator response. Among all subjects, FEV₁ decline was not different between augmentation-therapy groups (p  = 0.40). However, among subjects with a mean FEV₁ 35 to 49% predicted, FEV₁ decline was significantly slower for subjects receiving than for those not receiving augmentation therapy (mean difference = 27 ml/yr, 95% CI: 3 to 51 ml/yr; p = 0.03). Because this was not a randomized trial, we cannot exclude the possibility that these differences may have been due to other factors for which we could not control.