This study aimed to investigate the nature and effect of exacerbations in patients with alpha(1)-antitrypsin deficiency and to assess the impact of exacerbations on health status. Furthermore, the relationship of exacerbations to changes in lung function and health status was investigated. In total, 265 patients with severe deficiency (PiZ phenotype) were assessed over 12 months and a subgroup of 87 patients was studied for 3 yrs. Exacerbations were recorded and patients underwent full lung function testing and health status measurement. Exacerbations occurred in 142 patients (54%) over 12 months, with a median duration of 14 days (interquartile range 7-21). Health status was significantly worse in patients with exacerbations, especially those with frequent exacerbations. Neither the presence nor the frequency of exacerbations showed a relationship to decline in forced expiratory volume in one second, but the number of exacerbations was weakly associated with decline in gas transfer of the lung for carbon monoxide. Despite lung function decline, health status did not change significantly over 3 yrs. In conclusion, exacerbations occur commonly in patients with alpha(1)-antitrypsin deficiency and are associated with worse health status. Exacerbations were associated with a decline in the gas transfer of the lung for carbon monoxide over time, but show no relationship to changes in forced expiratory volume in one second. Despite lung function decline, patients do not show a progressive loss in health status.