Recently, it was suggested that peripherally-mediated analgesia can be accomplished by the intra-articular delivery of the mu-opioid morphine or of the a2-agonist clonidine. This clinical study assesses the potential peripheral analgesic effect of the combination of morphine and clonidine after intra-articular administration. Sixty patients (American Society of Anesthesiologists status I or II) undergoing arthroscopic repair of the knee during general anaesthesia were randomized to receive after operation, in a double-blind manner, either 1 μg morphine intra-articularly (group 1); 150 μg clonidine intra-articularly (group 2); or 1 μg morphine + 150 μg clonidine intra-articularly (group 3); or normal saline intra-articularly (group 4) in a volume of 30 mL, respectively. Visual analogue pain scores (VAS), duration of analgesia as defined by first demand for supplemental analgesics, subsequent 24 h consumption of postoperative supplementary supplementary analgesics, and patient satisfaction were evaluated. Co-administration of morphine + clonidine (group 3) resulted in a significant VAS reduction at 2 h after injection compared with the other groups. There was a tendency towards a lower need for supplementary rescue analgesia and towards a more prolonged analgesia in group 3 (211 min ± 224 min SD) compared with group 1 (173 min ± 197 min SD) and group 4 (91 min ± 21 min SD). More patients were very satisfied with the postoperative analgesic regimen receiving the combination of morphine and clonidine (group 3) at 24 h postoperatively. Thus we conclude, that the peripheral co-delivery of an opioid and an a2-agonist will result in improved postoperative pain relief, when compared with each single agent given alone.