Background: One common method of pain control for total shoulder arthroplasty is long-duration delivery of local anesthetic via interscalene brachial plexus block (ISB) with a continuous catheter. Alternatively, liposomal bupivacaine has also been administered as an ISB as a means to prolong the analgesic effect. This study was completed to measure the non-inferiority of single-injection ISB with liposomal bupivacaine compared with ISB continuous catheter for total shoulder arthroplasty. Methods: We performed a retrospective chart review of patients who underwent total shoulder arthroplasty using either an ISB continuous catheter or a single injection ISB with liposomal bupivacaine for post operative analgesia. The primary goal of this study was to determine if single-injection with liposomal bupivacaine conferred non-inferior pain scores compared to the continuous catheter. Secondary outcomes evaluated oxygen saturation as a measure of hemidiaphragmatic paresis, post operative opioid requirements, and difference in cost. Results: We identified 333 patients for the study: 126 received continuous catheter and 207 received single-injection with liposomal bupivacaine. The median length of stay was 1 day. Pain scores for those treated with single-injection with liposomal bupivacaine were non-inferior to pain scores of those treated with the continuous catheter on post-op days 0, 1 and 2. Pain scores were lower for single-injection with liposomal bupivacaine patients on days 3 and 4, however they did not reach statistical significance. There was no significant difference in oxygen saturation between the two groups. Both groups had similar daily morphine milligram equivalent requirements. Liposomal bupivacaine ISB was also found to be less expensive. Conclusion: Single-injection ISB with liposomal bupivacaine provides non-inferior analgesia at a reduced cost compared with continuous catheter ISB for total shoulder arthroplasty.