Background: Percutaneous nephrolithotomy surgery (PCNL)is preferably performed under spinal anesthesia (SA). Bezold -Jarisch reflex (BJR), is mediated by serotonin receptors (5-HT₃) located on the vagus nerve and within the wall of the cardiac ventricles, contributes to the occurrence of hypotension and bradycardia after SA. Ondansetron; an antiemetic drug was investigated as a 5-HT₃ antagonist for inhibition of BJR. Aim of the work: This study aims to assess the effect of Ondansetron on spinal-induced hypotension during PCNL surgery under SA. Patients and Methods: This prospective randomized double-blinded study included eighty-four patients scheduled for PCNL under SA in Urology and Nephrology center, Mansoura University. Patients were randomized into two equal groups: Group C (n=42 cases) and Group O(n=42 cases) which received IV ondansetron 4mg 5 minutes before SA. Results: No statistical difference regarding basal characteristics, perioperative SBP, DBP, the incidence of intraoperative hypotension, the required dose of ephedrine, frequencies of hypotension, and duration of each hypotensive episode was detected in our study. Conclusions: in our study, ondansetron 4mg IV 5 minutes before spinal anesthesia in cases of PCNL under SA using a bupivacaine-dexmedetomidine mixture didn't reduce the incidence of hypotension and didn't reduce the required dose of ephedrine