PURPOSE: To study the effects of 3 different intra-articular analgesic combinations on postoperative pain, and whether the timing of the injection, either preoperative or postoperative, had an effect on postoperative analgesia. TYPE OF STUDY: Prospective, randomized, double-blind clinical trial. METHODS: Patients undergoing knee arthroscopy performed by a single surgeon under general anesthesia were randomized into 6 study groups. Each patient received an intra-articular injection 20 minutes before incision and at the end of the procedure. One injection contained the study medications, and the other contained normal saline solution (placebo). The patients, surgeon, and data collection personnel were blinded to the contents of the injections. Outcome measures included visual analogue pain scores at 0, 60, and 120 minutes after the procedure, and total recovery room fentanyl consumption. RESULTS: Fifty patients successfully completed the study protocol. Patients receiving combinations of morphine, bupivacaine, and epinephrine or bupivacaine and epinephrine yielded lower pain scores and narcotics consumption than patients receiving epinephrine alone, which was statistically significant irrespective of the timing of injection (P < .0001). Patients receiving the study medication preoperatively had significantly lower pain scores at the first measurement (t = 0) than those receiving the study medication postoperatively (P = .0343). There was no statistically significant effect of timing of the treatment medication administration at either 60 or 120 minutes postoperatively. Comparison of fentanyl consumption between groups receiving the treatment medication preoperatively versus postoperatively showed no significant difference. CONCLUSIONS: The combination of morphine, bupivacaine, and epinephrine, as well as the combination of bupivacaine and epinephrine provide excellent postoperative pain control when used either preoperatively or postoperatively in knee arthroscopy. There was a trend that patients receiving preoperative analgesic injections experienced superior pain control than did those injected postoperatively. LEVEL OF EVIDENCE: Level I, Randomized Controlled Trial.