Management of postsurgical analgesia is an important consideration in orthopedic procedures, including joint arthroplasty. Inadequate postsurgical analgesia is associated with increased hospital length of stay, delayed ambulation, and reduced exercise capacity. In this article, we review the potential contribution of a prolonged-release liposomal formulation of bupivacaine as part of a multimodal analgesic regimen after orthopedic surgery. Controlled studies across multiple surgical settings have demonstrated that, compared with placebo and bupivacaine HCl, liposome bupivacaine in a single administration provides postsurgical analgesia for up to 72 hours, delays use of rescue medication, and reduces postsurgical opioid consumption. Liposome bupivacaine has been well tolerated in clinical studies and has had a low rate of treatment-related adverse events. To date, there has been no signal of cardiac toxicity, chondrolysis, or delayed wound healing associated with liposome bupivacaine.