We have theorized that a subset of PiZZ α1-antitrypsin (α1-AT)- deficient individuals is more susceptible to liver injury by virtue of second inherited trait(s) or environmental factor(s), which exaggerate the accumulation of mutant α1-AT Z within the endoplasmic reticulum (ER) of liver cells. Using a complementation approach in which cell lines from PiZZ individuals with liver disease ('susceptible' hosts) and from PiZZ individuals without liver disease ('protected' hosts) are transduced with the mutant α1-AT Z gene, we have recently shown that there is a delay in ER degradation of mutant α1-AT Z protein that is only present in cell lines from susceptible hosts and correlates with the liver disease phenotype. In the present study we examined the specificity of this ER degradation pathway to determine if it is responsible for degrading other misfolded mutants of α1-AT and/or for unassembled membrane proteins. The S mutant of α1-AT and H2a subunit of the asialoglycoprotein receptor (ASGPR H2a) were expressed in skin fibroblast cell lines from susceptible and protected hosts. The results showed in both susceptible and protected hosts that α1-AT S was associated with a delay in secretion as compared with wild type α1-AT. The α1-AT S mutant was retained in ER, albeit to a lesser extent than the α1-AT Z mutant. There was, however, a significant increase in retention of α1-AT S in the ER of susceptible as compared with protected host cells. The same host cell lines were transduced to express an unassembled membrane protein, ASGPR H2a. There was no difference in the kinetics of ER degradation of ASGPR H2a in susceptible as compared with protected hosts. Taken together, the results show that α1-AT S is associated with a defect in biogenesis, intracellular retention, which is similar to but milder than α1-AT Z. Like α1-AT Z, α1- AT S is degraded by a pathway in the ER, which is relatively inefficient in PiZZ individuals with the liver disease phenotype. However, this pathway appears to be different from that previously described for a model unassembled membrane protein.