Abstract Background Available screening procedures for the detection of α₁-antitrypsin-deficient (AATD) mutations have suboptimal cost-effectiveness ratios. The aim in this study was to evaluate and compare the viability of a composite approach, primarily based on the α₁-globulin fraction, in identifying AAT genetic analysis eligible patients against standard screening procedures, based on clinically compatible profiling and circulating AAT < 1 g/L. Methods A total of 21,094 subjects were screened for AATD and deemed eligible when meeting one of these criteria: α₁-globulin ≤2.6%; α₁-globulin 2.6%–2.9% and AST: >37 U/L and ALT: > 78 U/L; α₁-globulin %: 2.9–4.6% and AST: >37 U/L and ALT: >78 U/L and erythrocyte sedimentation rate (ESR) >34 mm/h and C-reactive protein (CRP) >3 mg/L. Subjects were genotyped for the AAT gene mutation. Detection rates, including those of the rarest variants, were compared with results from standard clinical screenings. Siblings of mutated subjects were included in the study, and their results compared. Results Eighty-two subjects were identified. Among these, 51.2% were found to carry some Pi*M variant versus 15.9% who were clinically screened. The detection rates of the screening, including relatives, were: 50.5% for the proposed algorithm and 18.9% for the clinically-based screening. Pi*M variant prevalence in the screened population was in line with previous studies. Interestingly, 46% of subjects with Pi*M variants had an AAT plasma level above the 1 g/L threshold. Conclusions A composite algorithm primarily based on the α₁-globulin fraction could effectively identify carriers of Pi*M gene mutation. This approach, not requiring clinical evaluation or AAT serum determination, seems suitable for clinical and epidemiological purposes.