A significant number of patients with degenerative arthritis of the knee require bilateral knee arthroplasty. Single-stage bilateral total knee arthroplasty (SBTKR) has been associated with increased patient morbidity and mortality. At our institution, the following steps have been taken to minimize the risks to patients undergoing this procedure: regional anesthesia and analgesia, invasive monitoring, postoperative observation in an intensive care unit setting, and aggressive management of hemodynamic aberrations. We reviewed the medical records of 462 sequential total knee arthroplasty patients, consisting of 169 SBTKR and 293 unilateral total knee arthroplasty (UTKR) cases. A total of 122 patients from each group were matched for age, weight, and a history of ischemic heart disease and hypertension. Patients for SBTKR exhibited a significantly higher incidence of fat embolism syndrome and cardiac arrhythmias than UTKR patients. There were no deaths in either group and the incidence of other serious postoperative complications was low and similar between the two groups. Elderly patients (∼75 years old) had more postoperative complications. With aggressive clinical management SBTKR can be safely performed in selected patients. Guidelines for the selection of these patients are presented.