Introduction: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition caused by SERPINA1 variants with variable severity. Current international guidelines do not recommend augmentation therapy for intermediate AATD; nevertheless, some patients show clinically severe phenotypes in real-world practice. We aimed to evaluate, in an exploratory manner, the potential effects of augmentation therapy on exacerbations, quality of life, and lung function in this subgroup. Methods: In this multicenter retrospective study, we included 27 heterozygous patients with intermediate AATD (serum AAT 50–110 mg/dL), Chronic Obstructive Pulmonary Disease (COPD), and/or emphysema. Clinical phenotypes included emphysema-predominant disease, COPD with frequent exacerbations, and overlap with bronchiectasis/asthma; HRCT patterns were recorded. We assessed the annual number of exacerbations (moderate: steroids/antibiotics; severe: hospitalization/including pneumothorax), St. George’s Respiratory Questionnaire (SGRQ), and lung function before and after 12 months of therapy. Results: Augmentation therapy was associated with a reduction in annual exacerbations from a median (IQR) of 2 (1.5–3) to 1 (0–1) (p < 0.0001) and an improvement in SGRQ total score (58.89 ± 16.83 to 48.34 ± 21.20; p = 0.0039). The mean SGRQ change exceeded the 4-point MCID for COPD. No significant changes were observed in spirometry or Diffusing Capacity of the Lung for Carbon Monoxide (DLCO). Conclusions: These exploratory findings suggest that augmentation therapy may reduce exacerbations and improve quality of life in selected patients with intermediate AATD and COPD/emphysema. Given the retrospective design, small sample, and lack of a control group, the results should be interpreted as hypothesis-generating and warrant confirmation in prospective studies.