Introduction Immunosuppression (IS) determines a higher risk of disease severity from Listeria monocytogenes (LM) infection. Methods We examined the epidemiology of IS in all patients hospitalized with LM in Spain from 2000 to 2021 in the National Registry of Hospital Discharges. IS was defined by liver disease (LD), diabetes mellitus (DM), chronic kidney disease (CKD), solid organ transplantation (SOT), bone marrow transplantation (BMT), primary immunodeficiencies (ID), systemic autoimmune diseases (SAD), solid organ neoplasms (SON), and hematological neoplasms (HN). Results Among 8,152 admissions with LM, 48% were IS. There was an increase from 39.5% to 60% during the study period, mainly driven by rises in DM (from 12.6% to 26.2%), SON (from 9.9% to 17.5%), CKD (from 4.4% to 16.3%), HN (from 6.6% to 13.4%), and LD (from 4.9% to 6.6%) (p < 0.001 for all trends). IS fatality rate was higher than in non-IS (22.4% vs 11.3%; OR = 2.09). The proportion of LM patients with IS among LM in-hospital deaths increased from 57.1% in 2000 to 67.95% in 2021 (p < 0.001). Fatality risk differed according to baseline IS condition: LD (OR = 2.42), CKD (OR = 1.49), SON (OR 3.01) and HN (OR 1.45). Conclusions The prevalence of IS among patients hospitalized with LM in Spain has risen over the past two decades, with a growing impact on fatality rates. These findings should prompt further efforts to prevent and manage properly LM infection.