Background: Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infectious disease of immunocompromised patients. Its incidence has decreased worldwide in the past, but data concerning its recent epidemiology are lacking., Methods: We retrospectively analyzed all German inpatient cases from January 1, 2014 to December 31, 2019, to describe the recent epidemiology, incidence, clinical course, mortality and underlying diseases of PCP. Simultaneously, we conducted a retrospective multi-center study at two German university hospitals, and analyzed PCP cases treated there to gain deeper insights on the basis of primary patient data., Findings: The incidence of PCP significantly increased from 2·3 to 2·6 per 100,000 population from 2014 to 2019 (1,857 to 2,172 cases, +17·0%, p < 0·0001), as well as PCP-related deaths (516 to 615 cases, +19·2%, p = 0·011). The spectrum of underlying diseases changed: Risk groups with established chemoprophylaxis for PCP based on international guidelines (HIV, hematologic malignancies, and transplantation) showed a significant decrease in PCP cases and deaths. Others, especially those with solid malignancies, and autoimmune and pulmonary diseases showed a significant increase in case numbers and deaths. Data from the retrospective multi-center study added information regarding prophylaxis and diagnostics of PCP., Interpretation: The incidence of PCP has reversed its trend, showing a significant increase in mortality on population level. Patients who were not previously considered in prophylactic measures are increasingly affected by PCP. This development deserves further investigation, and additional comprehensive guidelines for the use of chemoprophylaxis in new risk groups are needed., Funding: Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Kiel., Competing Interests: Kevin Schulte received honoraria for lectures from AstraZeneca, Novartis, Takeda Pharma and Vifor without relation to the study presented here. All other authors declare no competing interests., (© 2022 The Author(s).)