This report describes the clinical characteristics of a group of 59 individuals with the PI*SZ phenotype and alpha 1-antitrypsin (alpha 1-AT) deficiency, identified during recruitment of a registry for subjects with severe alpha 1-antitrypsin deficiency. Currently, 1,129 individuals with levels of alpha 1-AT of 11 microM or below have been enrolled in this registry. Individuals with the SZ phenotype whose alpha 1-AT levels are at or below 11 microM will be followed in the registry; those whose levels exceeded 11 microM had baseline studies and are included in this report. Baseline pulmonary function tests included spirometry before and after an inhaled bronchodilator, diffusing capacity for carbon monoxide (DLCO), and chest roentgenograms. Among nonsmokers, subjects with the SZ phenotype demonstrated airflow obstruction less frequently than those with with the ZZ phenotype. Among ex- and current smokers, the frequency and severity of airflow obstruction was similar between SZ and ZZ subjects. Individuals with the SZ phenotype reported respiratory symptoms less frequently than did ZZ subjects. Overall, airflow obstruction was less common and milder among PI*SZ than PI*ZZ subjects. Cigarette smoking correlated more strongly with airflow obstruction among PI*SZ than PI*ZZ subjects. These observations indicate that in smokers, the PI*SZ phenotype confers a significant risk of the development of chronic obstructive pulmonary disease (COPD). Of itself, except in rare instances in nonsmoking individuals, the PI*SZ phenotype may confer little or no added risk of developing COPD.