Sex differences have been observed in the antinociceptive effects of opioids in rodents and rhesus monkeys. Sex differences in the affinity of opioid ligands for opioid receptors may contribute to these findings. To test this hypothesis, the relative affinity of the competitive opioid antagonist quadazocine for mu and kappa opioid receptors was determined in rhesus monkeys using in vivo pA(2) analysis. The antinociceptive effects of the mu opioid agonist fentanyl and the kappa opioid agonist U50,488 were determined alone and after pretreatment with quadazocine in 4 females and 4 males using a warm-water tail-withdrawal assay of thermal nociception. The relative potency of quadazocine antagonism of fentanyl and U50,488 in females and males was used to assess sex differences in the relative affinity of quadazocine for mu and kappa receptors. Fentanyl was equipotent in female and male monkeys, and quadazocine was equipotent as an antagonist of fentanyl in females and males. In contrast, U50,488 was significantly less potent in females, and quadazocine was less potent as an antagonist of U50,488 in females. These findings suggest that opioid ligands have similar affinity for mu receptors but lower affinity for at least some kappa receptors in female than in male rhesus monkeys.