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The safety of bilateral total knee arthroplasties (BTKAs) during the same hospitalization remains controversial. The authors sought to study differences in perioperative outcomes between unilateral and BTKA and to further compare BTKAs performed during the same versus different operations during the same hospitalization.Nationwide Inpatient Sample data from 1998 to 2006 were analyzed. Entries for unilateral and BTKA procedures performed on the same day (simultaneous) and separate days (staged) during the same hospitalization were identified. Patient and healthcare system–related demographics were determined. The incidences of in-hospital mortality and procedure-related complications were estimated and compared between groups. Multivariate regression was used to identify independent risk factors for morbidity and mortality.Despite younger average age and lower comorbidity burden, procedure-related complications and in-hospital mortality were more frequent after BTKA than after unilateral procedures (9.45% vs. 7.07% and 0.30% vs. 0.14%; P < 0.0001 each). An increased rate of complications was associated with a staged versus simultaneous approach with no difference in mortality (10.30% vs. 9.15%; P < 0.0001 and 0.29% vs. 0.26%; P = 0.2875). Independent predictors for in-hospital mortality included BTKA (simultaneous: odds ratio, 2.23 [95% confidence interval, 1.69–2.95]; P < 0.0001; staged: odds ratio, 2.01 [confidence interval, 1.28–3.41]; P = 0.0031), male sex (odds ratio, 2.02 [confidence interval, 1.75–2.34]; P < 0.0001), age older than 75 yr (odds ratio, 3.96 [confidence interval, 2.77–5.66]; P < 0.0001), and the presence of a number of comorbidities and complications.BTKAs carry increased risk of perioperative morbidity and mortality compared with unilateral procedures. Staging BTKA procedures during the same hospitalization offers no mortality benefit and may even expose patients to increased morbidity.