The compatibility of a medication with other drugs and implanted materials is an important factor impacting drug safety and efficacy. The liposomal formulation of the local anesthetic bupivacaine is designed to provide prolonged postsurgical analgesia. Its compatibility with other drugs and materials depends on the compatibility of the drug itself, along with the integrity of liposome and liposomal components. A series of studies was conducted to evaluate the compatibility of liposome bupivacaine with diluents, implanted materials, and other drugs likely to be encountered in the surgical settings in which it is used. Liposome bupivacaine demonstrated compatibility with diluents (normal saline, lactated Ringer's solution) and with implanted materials (silicone, stainless steel, titanium, polypropylene, expanded polytetrafluoro-ethylene), with little or no change in percent of free bupivacaine, packed particle volume, or particle size distribution; liposome bupivacaine exhibited little or no change in the properties of the test materials. Liposome bupivacaine had clinically meaningful interactions with other local anesthetics, including lidocaine, ropivacaine, mepivacaine, or bupivacaine HCl (at liposome bupivacaine to bupivacaine HCl ratios < 2:1), which resulted in substantial displacement and release of free bupivacaine from liposomes. Liposome bupivacaine may be locally administered after ≥ 20 minutes following local administration of lidocaine, ropivacaine, or mepivacaine. Co-administration of liposome bupivacaine and bupivacaine HCl into the same site should be at ratios ≥ 2:1. Interactions between liposome bupivacaine and epinephrine, corticosteroids, antibiotics, non-steroidal anti-inflammatory drugs, tranexamic acid, and opioid analgesics were not clinically meaningful; liposome bupivacaine may be safely co-administered with these agents. No adverse synergistic effects on liposome bupivacaine were observed in evaluations involving multiple medications compared with each drug's individual effects.