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Background The safety of bilateral total knee arthroplasties (BTKA) during the same hospitalization remains controversial. We sought to study differences in perioperative outcomes between unilateral and BTKA, and further compare BTKAs performed during the same versus different operations during the same hospitalization. Methods 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 health-care system related demographics were determined. The incidence of in-hospital mortality and procedure related complications was estimated and compared between groups. Multivariate regression was used to identify independent risk factors for morbidity and mortality. Results 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: OR 2.23, CI=[1.69; 2.95], P<0.0001; staged: OR 2.01, CI=[1.28; 3.41], P=0.0031), male gender (OR 2.02, CI=[1.75, 2.34], P<0.0001), age above 75 years (OR 3.96 CI=[2.77, 5.66], P<0.0001), and the presence of a number of comorbidities and complications. Conclusion BTKAs carry increased risk of perioperative morbidity and mortality compared to unilateral procedures. Staging BTKA procedures during the same hospitalization offers no mortality benefit, and may even expose patients to increased morbidity.