Background: Postoperative pain relief is important in procedures of the lower extremity. Several previous studies have evaluated the efficacy of intra-articular (IA) pethidine as a compound, which has local anesthetic and opioid agonist properties, on postoperative pain relief in arthroscopic knee surgery (AKS). This study compared the postoperative analgesic effect of pre- and post-surgical IA pethidine administration in AKS. Materials and Methods: Seventy-five patients of American Society of Anesthesiologists (ASA) I and II undergoing AKS with general anesthesia were enrolled in this double-blind study. Patients were randomized in three equal groups to receive either 50 mg IA pethidine before surgical incision incision and saline after skin closure (PS), saline before surgical incision and pethedine after skin closure (SP), and only saline at two different times (SS). In each patient with operated knee joint, pain at rest and joint movement was evaluated at 1, 2, 6, 12, and 24 h after surgery completion using Visual Analog Scale (VAS). Data were analyzed using analysis of variance (ANOVA)-repeated measure, t-paired, and Chi-square tests. Results: Postoperative pain score at rest and joint movement in PS group was significantly lower than those in other groups. The time (Mean ± SD) between completion of operation and patient′s request for morphine, total morphine consumption (Mean ± SD) in postoperative 24 h, and the numbers of patients requesting analgesic in PS, SP, SS, groups were: 5.2 ± 1.3, 3.3 ± 1.5, and 2 ± 1.3 h (P < 0.05); 4.4 ± 2.4, 8.7 ± 2, and 11.6 ± 4.4 mg (P < 0.05); 11, 18, and 21 persons (P < 0.05), respectively. Conclusion: The present study shows that preemptive intra-articular pethidine 50 mg injection is more effective than preventive injection for postoperative pain relief at rest and joint movement in arthroscopic knee surgery.