Objectives: To analyze the number and clinical characteristics of hospital admissions in Spain between 2016 and 2022 in which alpha-1-antitrypsin deficiency (AATD) was coded; to describe and analyze differences in these parameters between men and women; and to identify variables associated with a worse prognosis. Methods: We used a nationwide discharge database to select all admissions featuring an AATD diagnostic code (ICD-10 code E88.01) in any position. Results: We found 5142 hospital admissions with a diagnosis of AATD and detected a significant increase in their number from 2016 to 2022 (p = 0.034 for trend). Males accounted for 58.21% of the hospitalizations and had a higher Charlson Comorbidity Index than women (1.86 vs. 1.33; p < 0.001), were hospitalized more frequently (21.18% of men were hospitalized more than once vs. 17.76% of women, p < 0.001), and had a higher probability of severe disease (OR 1.39; 95%CI 1.10–1.75). Crude in-hospital mortality (IHM) was 6.85% in men and 4.8% in women (p = 0.007). The variables associated with IHM in both sexes were older age, more hospital admissions, and liver disease or lung cancer. Invasive and non-invasive mechanical ventilation and admission to the ICU were also associated with IHM in men and women. Multivariable adjustment revealed no association between sex and IHM. Conclusions: The number of hospitalizations for AATD increased in Spain from 2016 to 2022. Men represented almost 60% of hospitalizations, were admitted more frequently and with more comorbidities, and had a higher probability of severe disease than women. There was no association between sex and IHM.