Background: Over the last century infectious diseases have been kept under control in industrialized countries thanks to advances in hygiene, prevention and antimicrobial treatments. However, the emergence of HIV, the COVID-19 pandemic, and the rise of resistant bacteria exemplify that infectious diseases continue to pose a global threat. A comprehensive understanding of the caseload, spectrum of infectious diseases and the economic impact they pose is required to develop strategies for managing infectious diseases in a resilient healthcare system. Objectives: (i) to determine the proportion of adult patients discharged from German hospitals with primary diagnoses classified as an infectious disease, (ii) to describe the clinical spectrum of these diagnoses, case characteristics, and hospital settings, and (iii) to estimate the total economic burden that these cases contribute to the in-patient sector of the healthcare system. Methods: A retrospective case-control study was performed using publicly available data on ICD10 codes assigned as primary diagnoses, case characteristics, treatment settings, and cost weights from all patients discharged from German hospitals in 2022. Results: 1,728,824 adult patients (12% of all adult patients) were discharged with a primary diagnosis classified as an infectious disease. They were assigned 912 individual ICD10 codes. The 15 and 79 most frequently used codes comprised 40% (top 40% ID population) and 80% (top 80% ID population) of all infectious disease cases, respectively. In the top 80% ID population, patients were older, were more likely to be male, and had higher complexity and comorbidity levels than the reference population, which consisted of all adult patients minus the patients in the top 80% ID population. The mean length of stay of patients forming the top 80% ID population was 8.0 days vs. 6.1 days in the reference population. The median (IQR) cost weight was 0.663 (0.544–1.030) translating into €2,541 per case. Conclusions: In Germany, patients with infectious diseases constitute a significant proportion of all inpatients, with a broad spectrum of conditions. These patients are generally older, more severely ill, and require longer hospital stays than those without a primary infectious disease diagnosis, contributing substantially to the overall economic burden on the healthcare system.