Abstract Treatment tailored to specific patient characteristics (i.e. precision medicine) has the potential to offer more effective options for post-operative pain management. Chronic pain conditions are a heavy burden to society due their economic impact and individual suffering they cause; and developing precision medicine approaches are a high priority for the Federal Pain Research Strategy. Accordingly, in this proposal, we will initiate a precision medicine approach for total shoulder arthroplasty by identifying a risk phenotype that is predictive of chronic post-surgical pain. Biologic, psychologic, and social factors (alone and in combination) will be considered as candidates for the risk phenotype. Additionally, changes in biochemical biomarkers and psychologic factors will be considered as post-operative time-varying factors to enhance predictive accuracy of the risk phenotype. This proposal will support a prospective cohort study of 461 individuals undergoing primary total shoulder arthroplasty (anatomic or reverse) at Duke Health. The primary outcome is chronic post- surgical pain 12-months after total shoulder arthroplasty. Risk phenotype measures will be collected pre- operatively and time-varying factors will be collected pre-operatively and post-operatively. We will investigate novel combinations of biologic, psychologic, and social factors to determine a chronic post-surgical pain risk phenotype for total shoulder arthroplasty. Additionally, time-varying factors will be tested for improving predictive accuracy of the risk phenotype. This proposal will advance the pain research field by addressing important knowledge gaps in chronic post-surgical pain development for adults with osteoarthritis that are undergoing a surgical procedure that is a) rapidly increasing in volume and b) has a high risk of post-operative pain. Successful completion of the study has the potential to alter standard of care for surgical selection and provide new avenues of precision medicine for post-operative pain management. Specifically, completion of this study may allow for risk stratification approaches that improve surgical decision making to be implemented in health care systems and/or identify novel treatment targets that could be tested for effectiveness in preventing chronic post-surgical pain.