Two prominent and important risk factors for nonmedical use of prescription opioids (NMUPO) identified in epidemiological studies are smoking status and sex (i.e., there is a greater likelihood of NMUPO in smokers and in men, relative to nonsmokers and women). Interestingly, nonsmokers and women are at greater risk for the aversive effects of postoperative nausea and vomiting. We have conducted six studies examining the subjective effects of oral oxycodone (0, 10, 20 mg) in samples that included both men and women and nonsmokers and light smokers (fewer than six cigarettes per day). Four groups were comprised of 115 volunteers: male smokers (n = 20), male nonsmokers (n = 38), female smokers (n = 15), and female nonsmokers (n = 42). We hypothesized that there would be an additive effect between smoking status and sex such that male smokers would experience less nausea and disliking, and greater overall liking, and that female nonsmokers would respond in the opposite fashion. As predicted, nausea and disliking ratings were lowest, and overall liking ratings the highest, in male smokers after oxycodone administration, whereas nausea and disliking ratings were highest, and overall liking ratings the lowest, in female nonsmokers. Thus, our hypotheses were generally supported, and suggest a possible biobehavioral mechanism for the epidemiological links between smoking status and sex and increased risk of NMUPO.