Background: Individuals with severe mental illness (SMI) have an increased risk for physical comorbidities, such as diabetes and cardiovascular disease, leading to reduced life expectancy. The overshadowing phenomenon is a major contributor to this health inequality, as clinical attention is predominantly focused on the management of psychiatric conditions, often to the detriment of physical health problems. PSY-KOMO aims at filling this gap by implementing an intervention focused on improving the prevention, detection and management of physical diseases in SMI patients through structuring the diagnostic approach of psychiatrists, providing patient navigators and building interdisciplinary health networks. Methods: The study design is a multicentre, non-randomized study with an intervention group (IG) receiving the new treatment PSY-KOMO care compared with a matched external control group (CG) (quasi-experimental design). Three endpoints are evaluated: (1) Improvement in the detection of physical diseases (incidence); (2) improvement in guideline-based treatment of the physical diseases; and (3) improvement of prevention and screening for physical diseases. These endpoints are compared between the IG and the external CG using regression analyses. Based on the sample size calculation, 1,302 participants with severe mental illness (SMI) were planned to be recruited for the intervention group (IG) to analyse the primary endpoint. Patients were included from four distinct regions in Germany: Frankfurt am Main, Neuss, Greifswald, and Göppingen. For analyses and matching of an external control group, data from the Association of Statutory Health Insurance Physicians are used. Discussion: The results will be used to evaluate the effectiveness of the PSY-KOMO intervention.   Trial registration: DRKS (DRKS - Deutsches Register Klinischer Studien)- Deutsches Register Klinischer Studien, DRKS00030200 registered on 27th January 2023.