Periarticular infiltration analgesia (PIA) is widely administered to relieve postoperative pain following total knee arthroplasty (TKA). The present study aimed to evaluate the effect of prolonging the analgesic duration by adding dexmedetomidine to PIA for pain management after TKA.One hundred and sixteen patients were randomly allocated into 3 groups based on PIA regimens including group R (ropivacaine), group E (ropivacaine plus epinephrine), and group D (ropivacaine plus dexmedetomidine). The primary outcomes were postoperative visual analog scale scores, time until the administration of first rescue analgesia, and opioid consumption. The secondary outcomes included postoperative inflammatory biomarkers and functional recovery. The tertiary outcomes were postoperative complications and adverse events.The patients in group D had significantly lower resting visual analog scale scores than those in groups R and E at 6 hours after surgery. Group R showed the higher pain scores at rest and motion than groups D and E 12 hours postoperatively. The use of dexmedetomidine or epinephrine postponed the time until the administration of first rescue analgesia and led to lower opioid consumption in the first 24 hours after TKA. The levels of interleukin-8 and tumor necrosis factor-α in groups D and E were significantly lower than those in group R on postoperative day 3. Furthermore, no significant differences were observed in functional recovery, postoperative complications, or adverse events among the three groups.Adding dexmedetomidine as an adjuvant to PIA could potentiate and prolong the analgesic effect in the early stage following TKA without increasing the risk of adverse events.Copyright © 2023 Elsevier Inc. All rights reserved.