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The purpose of this investigation was to determine the incidence rates of, and identify risk factors for, thirty-day postoperative mortality and complications among more than 15,000 patients who underwent a primary unilateral total knee arthroplasty as documented in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP).The NSQIP database was queried to identify patients who had undergone primary unilateral total knee arthroplasty between 2006 and 2010. Patient demographics, medical history, and surgical characteristics were recorded, as were thirty-day postoperative complications, mortality, and length of hospital stay. Complications were divided into categories, which included major systemic complications (complications requiring complex medical intervention) and major local complications (including deep wound infection and peripheral nerve injury). Univariate testing and multivariate logistic regression analysis were used to identify significant independent predictors of the outcome measures.A total of 15,321 individuals underwent primary unilateral total knee arthroplasty. The mean age (and standard deviation) of the patients was 67.3 ± 10.2 years. Obesity (a body mass index [BMI] of ≥30 kg/m2) was documented in 61.2% of cases, 18.2% of patients had diabetes, and 50% were graded as Class 3 or higher on the basis of the American Society of Anesthesiologists (ASA) classification system. The thirty-day mortality rate was 0.18%, and 5.6% of the patients experienced complications. Patient age (odds ratio [OR] = 1.12; 95% confidence interval [CI] = 1.06 to 1.17) and diabetes (OR = 2.99; 95% CI = 1.35 to 6.62) were independent predictors of mortality. A BMI of ≥40 kg/m2 was an independent predictor of postoperative complications (OR = 1.47; 95% CI = 1.09 to 1.98). Patient age of eighty years or older, an ASA classification of ≥3, and an operative time of >135 minutes influenced the development of any postoperative complication as well as major and minor systemic complications. Cardiac disease (OR = 4.32; 95% CI = 1.01 to 18.45) and a BMI of ≥40 kg/m2 (OR = 2.01; 95% CI = 1.02 to 3.97) were associated with minor local complications.Patient age and diabetes increased the risk of mortality after primary total unilateral knee arthroplasty. Predictive factors impacting the development of postoperative complications included an ASA classification of ≥3, increased operative time, increased age, and greater body mass.Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.