Several variables have been reported to affect the expression of sex differences in the analgesic potency of morphine. Although the effect of genetic background on morphine analgesia has been well documented, the relevance of genotype to sex differences in morphine analgesia has rarely been considered. The present study investigated morphine dose-response relationships in male and female mice of 11 inbred mouse strains on the tail-withdrawal test after i.c.v. administration. Large differences in morphine analgesic potency were observed between strains, reflecting the important influence of genotype on this trait. We identified three strains (AKR/J, C57BL/6J, and SWR/J) in which males displayed approximately 3.5- to 7.0-fold greater sensitivities to the analgesic effects of morphine than did their female counterparts. In contrast, in the CBA/J strain, females were found to be approximately 5-fold more sensitive to morphine than were the males. In all other strains, morphine potency estimates between the sexes were not statistically different. These data support the importance of genotype, sex, and their interaction in the mediation of morphine analgesia and suggest that equivocal findings regarding opioid sex differences in the literature may be partially accounted for by the use of different subject populations. The fact that female mice of the AKR/J and CBA/J strains exhibit 35-fold different morphine analgesic potency and that males of these strains are equally sensitive should facilitate the mapping and identification of sex-specific genes of relevance to morphine analgesia.