Background: Postoperative pain control after abdominally based autologous microvascular breast reconstruction is critical to functional recovery, patient satisfaction, and early discharge. The transversus abdominis plane block using 0.25% bupivacaine hydrochloride has been shown to be effective, but it is limited by a short duration of effect. Liposomal bupivacaine is a recently U.S. Food and Drug Administration-approved preparation of bupivacaine that can provide up to 72 hours of pain relief. The purpose of this randomized, controlled trial was to compare the analgesic efficacy of liposomal bupivacaine and conventional bupivacaine. Methods: This study was a prospective, single-blind, randomized, controlled trial of 44 patients undergoing abdominally based autologous breast reconstruction between June of 2016 and February of 2018 performed by a single surgeon. Each patient was randomized to receive either 266 mg of liposomal bupivacaine or 75 mg of conventional bupivacaine to the transversus abdominis plane at the conclusion of the reconstruction procedure. All patients were managed postoperatively according to an enhanced recovery protocol. Results: In our study of 44 patients, 22 patients received a transversus abdominis plane block with conventional bupivacaine and 22 patients received liposomal bupivacaine. There were no significant differences with regard to any outcome measure. No differences were found in total opioid consumption (p = 0.98), Quality of Recovery-15 scores (p = 0.72), pain scores (p = 0.39), or length of stay (p = 0.20). Conclusion: In the setting of a robust enhanced recovery after surgery protocol, liposomal bupivacaine does not confer advantages over conventional bupivacaine when used as single injections in transversus abdominis plane blocks after abdominally based microvascular breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.