BACKGROUND: The NMDA receptor mediates wind-up and long-term potentiation in the responses of cells to prolonged stimuli; thus we postulated that the induction and maintenance of sensitization would be affected by the timing of epidural ketamine administration under epidural anesthesia. METHODS: Sixty patients undergoing elective cesarian section were randomly and equally assigned to one of three groups. 20 ml of 2% lidocaine and 2 mg morphine with epinephrine was injected to all patients epidurally through an indwelling catheter inserted at the L2-3 interspace. Before surgical incision, the patients in group 1 were given 3 ml saline, while the patients in group 2 were given 30 mg ketamine. In group 3, patients were injected with 30 mg ketamine after peritoneal closure. An additional 2 mg morphine was injected into all patients 24 h after surgery. The analgesic effects were assessed and side effects were also evaluated. RESULTS: VAS of group 3 at 3 24 h was lower than in the group 1, and at 6 24 h it was lower than in the group 2. The number of patients using additional analgesics in group 3 was lower than in the other groups. The incidence of nausea and vomiting was higher in the group 1 than in the other groups, but dizzness was higher in the groups 2 and 3 than in the control group. CONCLUSIONS: Preoperative administration of epidural ketamine is less effective in reducing postoperative pain than when given after peritoneal closure, especially under epidural anesthesia with local anesthetics.