OBJECTIVE: Magnesium is an endogenous voltage-dependent NMDA receptor-channel blocker and ketamine is a non-competitive NMDA receptor antagonist. Magnesium may potentiate the effect of ketamine in analgesia and anaesthesia, but may also interact in an opposing manner. This study aimed at evaluating type of the interaction between magnesium sulphate and ketamine administered systemically in rats with an acute nociceptive pain (tail-immersion test). MATERIALS AND METHODS: Analgesic activity was assessed by tail-immersion test in male Wistar rats (200-250 g). The distal 5 cm of the tail was immersed in a warm water bath (55 ± 0.5°C) and the time for tail-withdrawal was measured as response latency. RESULTS: Magnesium sulphate (2.5-30 mg/kg, s.c.) and ketamine (2.5-30 mg/kg, i.p.) administered alone did not produce any effect. However, significant antinociception (synergistic interaction) was revealed at the following doses of ketamine: magnesium sulphate of 5:5 mg/kg, 2.5:5 mg/kg and 10:5 mg/kg. The effect was not dose-dependent, and a greater response was obtained when ketamine was administered before magnesium sulphate. CONCLUSIONS: This study revealed that (1) magnesium sulphate and ketamine given alone were not effective against acute nociceptive pain in rats, but (2) a combination of both drugs resulted in synergistically inhibited nociception, (3) which occurred only at selected low doses and proportions of the medications in a combination and (4) suggested the importance of the order of drug administration.