BACKGROUND: While some trials suggest benefits of liposomal bupivacaine, data on real-world use and effectiveness is lacking. We aimed to study the impact of liposomal bupivacaine use (regardless of administration route) on inpatient opioid prescription, resource utilization and opioid-related complications among patients undergoing total knee arthroplasties with a peripheral nerve block. We hypothesized that liposomal bupivacaine has limited clinical influence on the studied outcomes. METHODS: We included data on 88,830 total knee arthroplasties performed with a peripheral nerve block (Premier Healthcare Database 2013–2016). Multilevel multivariable regressions measured associations between use of liposomal bupivacaine and (1) inpatient opioid prescription (extracted from billing), length and cost of hospitalization, and (2) opioid-related complications. To reflect the difference between statistical and clinical significance we assumed a relative change of −15% in outcomes to be clinically important. RESULTS: Overall, liposomal bupivacaine was used in 21.2% (n=18,817) of patients that underwent a total knee arthroplasty with a peripheral nerve block. Liposomal bupivacaine use was not associated with clinically meaningful reduction in inpatient opioid prescription (group median 253 mg oral morphine equivalents, adjusted effect −9.3% CI 11.1%; −7.5% P