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Advances in clinical immunosuppression and characterization of optimal donor genetics continue to move the field of xenotransplantation toward a clinical reality. Cardiac xenograft survival in a non-life supporting heterotopic model has been extended to greater than 900 days as previously described by our lab. Orthotopic life supporting models for cardiac xenografts are being developed with the major barrier being significant peri-operative mortality. We detail the development of an orthotopic pig-to-baboon cardiac xenotransplant model, offering insights gained over time for replication of the model.Specific pathogen free baboons were transplanted with GTKO.CD46 donor pig hearts in the orthotopic position (n = 3) by cardiac transplant and congenital cardiac surgeons. The clinical team also included a perfusionist and cardiac anesthesiologist. Detailed reports were generated regarding equipment and medications required for the cases to approximate clinical orthotopic cardiac transplantation. Monitoring capabilities were optimized as well as resuscitative access and strategy. These baboons were recovered from prior experiments and per institutional protocol were approved for non-survival studies; cases were performed with intended short term survival under anesthesia followed by elective euthanasia.All recipient baboons were transplanted and weaned off of cardiopulmonary bypass with life sustaining cardiac function. Low dose inotropic support was continued in all cases; vasopressor support was continued in one case. Two cases were electively terminated after wean from bypass; one recipient suffered arrest three hours post wean from bypass. Recipients were monitored using femoral arterial lines, transesophageal echocardiogram, external EKG, continuous pulse oximetry, and serial bloodwork including ABG, CBC, BMP, and ACT. Central venous access with multiple lumens was critical to post-operative care. Invasive hemodynamic monitoring, pretreatment with anti-arrhythmics, and availability of cardioversion for the donor pig allowed rapid reversal of fibrillation episodes during procurement. Ideal cold ischemia time was found to be close to one hour; shorter ischemia time resulted in poorer xenograft function (n = 1) as evidenced by difficult wean from bypass and persistent need for vasopressor support. Atrial and ventricular pacing wires proved integral to the cardiopulmonary bypass weaning process.Cardiac xenotransplantation is a potential solution to the paucity of human organs. Technical refinement of the life-supporting orthotopic cardiac xenotransplant with expert clinical help and applying human standards of post-operative care are the critical next step toward a clinical reality. Here we detail our experience developing an operative and critical care approach to the orthotopic cardiac xenotransplantation model.