Background <p>Postoperative pain management after cardiac surgery involves a multimodal approach. Recently, the erector spinae plane (ESP) block has been incorporated into multimodal pain control protocols. These measures have been taken to increase patient satisfaction while minimizing opioid usage. Prospective data is lacking to guide decisions regarding optimal regional anesthetic agents. This randomized controlled pragmatic trial protocol seeks to determine the benefit of liposomal bupivacaine relative to plain bupivacaine hydrochloride at reducing postoperative opioid consumption and other clinical outcomes following cardiac surgery.</p> Methods <p>The investigators anticipate consenting 150 subjects to obtain 96 evaluable subjects undergoing minithoracotomy (<i>N</i> = 24 liposomal bupivacaine, <i>N</i> = 24 bupivacaine hydrochloride) or open sternotomy (<i>N</i> = 24 liposomal bupivacaine, <i>N</i> = 24 bupivacaine hydrochloride). The primary outcome will be postoperative opioid consumption, reported in morphine equivalents. Secondary outcomes will include postoperative nonopioid analgesic consumption, inpatient and outpatient postoperative pain scores, 30-day mortality and major morbidity rates, postoperative quality of life, and hospitalization costs. Double blinding will be conducted with necessary measures taken to mask electronic medical records and drug preparation.</p> Discussion <p>The trial is currently enrolling subjects at a single academic medical center in the northeastern United States. The current study aims to investigate the postoperative pain reported by patients undergoing cardiac surgery when receiving ESP blocks with liposomal bupivacaine (experimental) compared to its hydrochloride formulation (control).</p> Trial registration <p>ClinicalTrials.gov NCT06077422. Registered on October 2023.&#xa0;<a href="https://clinicaltrials.gov/study/NCT06077422?tab=table">https://clinicaltrials.gov/study/NCT06077422?tab=table</a>.</p>