Background and objectives Alpha-2 Macroglobulin (A2M) is a plasma protein with proteolytic effects on many proteases. In patients with an inborn alpha-1 antitrypsin deficiency (AATD) the homeostasis between proteases and antiproteases is disturbed. The aim of this study was to compare the levels of AAT and A2 M in patients and controls. We hypothesized that in patients with AATD A2 M levels are elevated. Methods Patients with AATD (polymorphism Pi*ZZ, Pi*SZ, Pi*MZ and rare gene variants) as well as healthy volunteers (Pi*MM) were tested for A2 M and AAT levels. The concentration of the proteins was measured by nephelometry. The polymorphisms Pi*Z and Pi*S were detected by polymerase chain reaction (PCR), the rare genetic variants were identified by sequencing. Results In our study, a total of 291 individuals were included. It could be shown that a significant increase in A2 M levels in the serum could be observed in the presence of a gene polymorphism (Pi*ZZ) and an alpha-1 antitrypsin serum level < 50 mg/dl compared to the healthy volunteers. Conclusions In this study, an inverse correlation between the serum levels of AAT and A2 M was found in the presence of a gene polymorphism (Pi*ZZ). Further studies are necessary to elucidate the clinical significance of increased A2 M serum levels in patients with severe AAT deficiency Pi*ZZ and rare gene variants whose AAT serum level is < 50 mg/dl.