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Postoperatively, transplant recipients receive immunosuppressants, as well as sedatives and analgesics. The immunomodulatory effects of these other agents during the induction period following transplantation remain unclear. We aimed to determine whether the agents dexmedetomidine hydrochloride (Dex) and fentanyl (Fen) have immunomodulatory effects during the induction period following heart transplantation (HTx).Fifty mice were used for antinociception tests after administration of Dex and Fen, and T cells from 3 naive animals were used for in vitro lymphocyte transformation test (study 1). Fifty-four B6 mice received HTx from BALB/c mice and were treated with Dex, Fen, or neither (study 2). Thirty-six recipients were used for graft survival data and were humanely killed at the time of cessation of heart graft contraction. The remaining 18 were humanely killed at either postoperative day (POD) 4 or 6 for histologic examination of graft survival, as well as in vitro analysis.Based on the results of study 1, daily intraperitoneal administration of Dex at 30 μg/kg or Fen at 0.25 mg/kg was determined to be the optimal dose to induce analgesia without oversedation following HTx. Graft survivals in both Dex- or Fen-treated animals were statistically prolonged compared with control (P < 0.01). Graft survival of Fen-treated recipients was increased up to 15 days, and graft survival of Dex-treated animals was also increased up to 10 days, whereas control mice rejected heart grafts by POD 7. Mixed lymphocyte reaction responses on POD 4 showed statistically lower responses in Dex-treated recipients and Fen-treated recipients when compared with controls (P < 0.01). Cytokine profiles of splenocytes showed markedly fewer interferon γ–positive splenocytes in Fen-treated recipients on POD 4.These data suggest that both Dex and Fen have immunomodulatory properties in the induction period following transplantation.