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Introduction and Objective: The aim of the study was to investigate the effect of bee venom on the activity of two analgesics: ketoprofen (a non-steroidal anti-inflammatory drug) and tramadol (an opioid drug) in the acute thermal pain model (hot-plate test) in mice., Material and Methods: Linear regression analysis was used to evaluate the dose-response relationship between logarithms of drug doses and their resultant maximum possible anti-nociceptive effects in the mouse hot-plate test. Doses that increased the anti-nociceptive effect by 20% (ED 20 values) for bee venom, ketoprofen and tramadol, and their combination were calculated from linear equations. The interaction between bee venom and the selected anaglesics was evaluated using isobolographic analysis., Results: The study showed that all compounds produced a definite anti-nociceptive effect, and the experimentally-derived ED 20 values for bee venom, ketoprofen and tramadol, when applied indivisually, was 3.64 mg/kg, 79.88 mg/kg and 13.26 mg/kg, respectively. Isobolographic analysis revealed that the combination of bee venom and ketoprofen at a fixed ratio of 1:1 was supra-additive (synergistic). The experimentally-derived ED 20 mix was 26.33 mg/kg, which significantly differed from the ED 20 add of 41.76 mg/kg (p < 0.5). The experimentally-derived ED 20 mix of bee venom and tramadol was 2.90 mg/kg, and differed significantly from the theoretically estimated ED 20 add of 8.45 mg/kg (p < 0.5), also indicating a synergistic interaction in the hot-plate test in mice. Moreover, none of the tested combinations indicated any adverse effects in the chimney test and the grip-strength test in mice., Conclusions: Overall, the obtained results demonstrated that bee venom significantly increased the anti-nociceptive activity of ketoprofen and tramadol in the hot-plate model of nociceptive pain in mice.