The rewarding property of opioids likely contributes to their abuse potential. Therefore, determining the genetic basis of opioid reward could aid in understanding the neurobiological mechanisms of opioid addiction, provided that it is a heritable trait. Here, we characterized the rewarding property of the widely abused prescription opioid oxycodone (OXY) in the conditioned place preference (CPP) assay using LG/J and SM/J parental inbred mouse strains and 17 parent–offspring families of a LG/J × SM/J F47/F48 advanced intercross line (AIL). Following OXY training (5 mg/kg, i.p.), SM/J mice and AIL mice, but not LG/J mice, showed an increase in preference for the OXY-paired side, suggesting a genetic basis for OXY-CPP. SM/J mice showed greater locomotor activity than LG/J mice in response to both saline and OXY. LG/J, SM/J, and AIL mice all exhibited robust OXY-induced locomotor sensitization. Narrow-sense heritability (h2) estimates of the phenotypes using linear regression and maximum likelihood estimation showed good agreement (r = 0.91). OXY-CPP was clearly not a heritable trait whereas drug–free- and OXY-induced locomotor activity and sensitization were significantly and sometimes highly heritable (h2 = 0.30–0.84). Interestingly, the number of transitions between the saline- and OXY-paired sides emerged as a reliably heritable trait following OXY training (h2 = 0.46–0.66) and could represent a genetic component of drug-seeking behavior. Thus, although OXY-CPP does not appear to be amenable to genome-wide quantitative trait locus mapping, this protocol will be useful for mapping other traits potentially relevant to opioid abuse.