Individuals who are homozygous for the protease inhibitor phenotype Z (PiZ) genetic variant of alpha 1-antitrypsin (alpha 1-AT) have reduced plasma concentrations of alpha 1-AT, and are susceptible to premature development of pulmonary emphysema. A subset of this population develops chronic liver disease. The reduction in plasma concentrations of alpha 1-AT results from a selective defect in secretion as the abnormal PiZ alpha 1-AT protein accumulates within the cell. It has recently been shown in several experimental systems that the heat shock/stress response, a response characterized by the synthesis of a family of highly evolutionarily conserved proteins during thermal or chemical stress, may also be activated by the presence of abnormal proteins within the cell. Therefore, we predicted that the heat shock/stress response would be induced in the absence of thermal or chemical stress in alpha 1-AT-synthesizing cells of PiZZ individuals. In the following study, however, we show that net synthesis of proteins in the heat shock/stress gene family (SP90, SP70, ubiquitin) is increased only in a subset of the population, PiZZ individuals with liver disease. It is not significantly increased in PiZZ individuals with emphysema or in those without apparent tissue injury. Net synthesis of stress proteins is not increased in individuals with another variant of the alpha 1-AT gene (PiS alpha 1-AT) and is not increased in individuals with severe liver disease but a normal alpha 1-AT haplotype (PiM alpha 1-AT). These results demonstrate that the synthesis of stress proteins is increased in a subset of individuals with homozygous PiZZ alpha 1-AT deficiency, those also having liver disease.