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SUMMARY Objective To determine whether submucosal mesna ( 2-mercaptoethane sodium sulfonate) infiltration is superior to normal saline or adrenaline + lidocaine in mucoperichondrial hydrodissection. Methods Twenty-one rabbits were administered adrenaline + lidocaine, saline or mesna. Bilateral septal mucoperichondrial flap elevations were performed following submucosal infiltration. The intraoperative bleeding amount, operation time, accessibility of the surgical plane, field quality and degree of mucoperichondrial injury were recorded. The three groups were compared histopathologically. Results The amount of bleeding and duration of the operation were significantly higher and the accessibility of the surgical plane score was significantly lower in the saline group vs. the other groups (p < 0.05). The mucosal damage rate was significantly higher in the saline group compared with adrenaline + lidocaine (p < 0.05). The surgical field quality was significantly lower in the saline group compared with adrenaline + lidocaine (p < 0.05). The accessibility of the correct surgical plane score was significantly lower in the saline group compared with the adrenaline + lidocaine and mesna groups (p < 0.05). The amount of bleeding, duration of operation, surgical field quality and accessibility of the surgical plane did not differ significantly between the adrenaline + lidocaine and mesna groups (p > 0.05). The pericondrium thickness was significantly lower in the saline group than the other groups. Cartilage thickness was significantly higher in the saline group compared with the mesna group (p > 0.05). Conclusion Use of mesna instead of normal saline or adrenaline + lidocaine in septoplasty was not more advantageous in terms of intraoperative parameters. The adrenaline + lidocaine group was superior to normal saline for all intraoperative parameters. In conclusion, the use of adrenaline may be more advantageous in facilitating septal mucoperichondrium elevation due to its widespread use, low cost and superiority to physiological saline.