This study was conducted in order to evaluate whether or not caffeine has any effect on venlafaxine antinociception in mice in acute application. Swiss albino mice, both male and female, were tested with hot plate analgesiameter set at 52.5 +/- 0.1 degrees C. The mice were divided into four groups receiving saline + saline, caffeine (5 mg/kg) + saline, saline + venlafaxine (70 mg/kg) and caffeine (5 mg/kg) + venlafaxine (70 mg/kg) intraperitoneally. Each animal was tested on hot plate before treatment and 30, 45, 60 min after injections. Venlafaxine produced a significant antinociceptive effect at 30 and 45 min and the effect decreased at 60 min. Caffeine alone showed no significant antinociceptive effect at the applied dose however, it significantly antagonized the antinociceptive effect of venlafaxine at 30 min. As a result, caffeine inhibits the antinociceptive effect of venlafaxine in acute application in mice and this observation provides new evidence that the adenosinergic system may play a significant role in the mechanism of antinociceptive action of venlafaxine. This study raises the possibility that caffeine consumption might influence the effectiveness of venlafaxine in the treatment of pain in humans.