Severe alpha 1-antitrypsin (alpha 1-AT) deficiency is characterized by a decrease in serum alpha 1-AT to values < 20% of normal. Severe airflow obstruction, most commonly due to pulmonary emphysema secondary to the destruction of pulmonary elastic tissue, may develop at an early age in persons with alpha 1-AT deficiency. The purpose of this study was to estimate the annual decline in FEV1 (delta FEV1) in alpha 1-AT-deficient patients, to compare delta FEV1 in a referral population (index cases) with subjects found through family studies (nonindex cases), and to evaluate the role of smoking cessation on delta FEV1. One hundred and sixty-one subjects from the Danish alpha 1-AT-deficiency study who were older than 25 yr and who had a recorded smoking history and at least two spirometric examinations 1 yr apart were studied. The delta FEV1 for each individual was determined by regression analysis of FEV1 on follow-up time. The overall mean delta FEV1 was 81 ml/yr. There was no significant difference in delta FEV1 between 113 index cases and 48 nonindex cases even after controlling for age, initial FEV1, sex, and lifetime tobacco consumption. One hundred of the subjects were ex-smokers, 18 had never smoked, and 43 were current smokers. The mean delta FEV1 among the current smokers was 132 ml/yr, versus 52 ml/yr among the ex-smokers (p < 0.001). For the never-smokers, the mean delta FEV1 was 86 ml/yr.