BACKGROUND: The use of multimodal pain regimens has been shown to be an effective technique for the treatment of postoperative pain after total knee arthroplasty. Periarticular injections, of both short-acting and long-acting anesthetics, have emerged as an additional method of providing significant improvement in postoperative pain relief. The purpose of this study is to compare the efficacy of periarticular injection using long-acting vs short-acting preparations. METHODS: A randomized, prospective study of 80 consecutive patients was performed comparing liposomal bupivacaine vs plain bupivacaine periarticular injection. The primary outcomes included pain relief, total narcotic usage, and completion of physical therapy goals, specifically range of motion. RESULTS: No significant improvements were noted between liposomal bupivacaine and plain bupivacaine injection groups in overall pain reduction, range of motion, or total narcotic usage. At 24 hours, small statistically significant differences in physical therapy pain scores were noted with liposomal bupivacaine vs plain bupivacaine and control patients, but these differences did not persist at later time points. Both preparations demonstrated statistically significant improvements in range of motion when compared to historical controls, but no differences were noted between preparations. CONCLUSION: Overall, minimal significant differences were noted between liposomal bupivacaine and plain bupivacaine at early and late time points. Both preparations of periarticular injection demonstrated superiority over control pain regimens but were relatively equivalent to one another in direct comparison.