The present study examined the influence of sex on the antinociceptive effects of (−)-pentazocine, morphine and spiradoline in four rat strains, using a warm-water (50, 52 and 55°C) tail-withdrawal procedure.In F344, Lewis, Sprague–Dawley (SD) and Wistar rats, baseline latencies decreased with increases in water temperature, and at each water temperature latencies were longer in males than in their female counterparts. Morphine and spiradoline produced maximal or near maximal antinociceptive effects in males and females of each strain. Whereas morphine was generally more potent in males, sex differences were not consistently observed with spiradoline. In contrast, there were marked sex differences with (−)-pentazocine, and in each strain (−)-pentazocine was more potent and produced a greater maximal effect in males. The magnitude of the sex differences varied markedly across strains, with (−)-pentazocine being 2.5-fold more potent in males of the F344 strain, but 11-fold more potent in males of the Wistar strain. When collapsed across nociceptive stimulus intensities, sex differences were largest in the Wistar and Lewis strains and smallest in the SD and F344 strains.The present findings indicate that there are marked sex differences in (−)-pentazocine antinociception, and that the magnitude of this effect is genotype dependent.