BACKGROUND: This paper describes an innovative cluster randomized controlled trial design to evaluate the comparative effectiveness of two approaches to preventing significant destabilization, leading to unplanned hospitalization and increased disability for patients with high comorbidity, that is, multiple chronic diseases defined by an enhanced Charlson Comorbidity Index ‚â•4. METHODS: A total of 1974 patients were randomized in four waves at each of the sixteen Federally Qualified Health Centers (FQHCs) in four health systems -two in New York and two in Chicago. The two interventions compared 1) Patient-Centered Medical Home (PCMH) as implemented by the FQHCs (usual care control); or 2) PCMH plus a coaching intervention delivered by Health Coaches (experimental) helping patients identify life goals to encourage self-management enhanced by a positive affect/self-affirmation strategy. The two primary patient-centered clinical outcomes are 1) Unplanned hospitalizations; and 2) Within-patient changes in quality of life and disability, as measured by the World Health Organization Disability Assessment Scale 2 (WHODAS 2.0). The hypotheses are: 1) intervention patients will have a 5 % relative reduction in unplanned hospitalizations as compared to control patients; and 2) reduced disability measured by WHODAS2.0; 3) destabilization or 'tipping points' leading to hospitalization will be more often triggered by psychosocial issues than by medical Issues. CONCLUSION: This cluster RCT has the potential to transform the care for patients with high comorbidity by helping motivate patients to engage in self-management and to successfully navigate the barriers, challenges, and stresses leading to destabilization, hospitalization, and increased disability. CLINICALTRIALS: gov registration number: NCT04176510.