BACKGROUND Perioperative nerve injury (PNI) is one of the most debilitating complications after total knee arthroplasty (TKA). Although regional anesthesia (RA) techniques reduce pain and improve functional outcomes after TKA, they may also contribute to PNI. The objective of this study was to test the hypothesis that PNI risk differs among patients according to RA use during TKA. METHODS All patients aged at least 18 yr who underwent elective TKA from January 1988 to July 2007 were retrospectively identified. The primary outcome variable was the presence of a new PNI documented within 3 months of the procedural date. Age, sex, body mass index, type of procedure, tourniquet time, type of anesthesia, and use of peripheral nerve blockade were evaluated as potential risk factors for PNI using multivariable logistic regression. RESULTS Ninety-seven cases of PNI were identified among 12,329 patients. Overall incidence of PNI was 0.79% (95% CI, 0.64-0.96%). PNI was not associated with peripheral nerve blockade (odds ratio [OR], 0.97) or type of anesthesia (OR, 1.10 [neuraxial vs. general]; OR, 1.82 [combined vs. general]). Risk for PNI decreased with age (OR, 0.68 [per decade]; P < 0.001) but increased with tourniquet time (OR, 1.28 [per 30-min increase]; P = 0.003) and bilateral procedures (OR, 2.51; P < 0.001). Patients with PNI who underwent peripheral nerve blockade were less likely to have complete neurologic recovery (OR, 0.37; P = 0.03). CONCLUSIONS Risk for PNI after TKA was unchanged by the use of RA techniques. This finding supports the notion that the known benefits of RA for patients undergoing TKA can be achieved without increasing risk of neurologic injury. However, in rare situations when PNI occurs, complete recovery may be less likely if it develops after peripheral nerve blockade.