The mu-opioid receptor (OPRM1) is expressed in brain regions implicated in reward and locomotor processes. Reduced reward, not only from opiates, but also from several other abused substances has been observed in mice with lifelong deletions of the OPRM1 gene. To further define the roles of mu-opioid receptors in psychostimulant actions, cocaine psychomotor stimulant and rewarding effects were examined in wild-type (WT), heterozygous and homozygous mu-opioid receptor knockout mice. While mu-opioid receptor knockout did not affect basal locomotion, locomotor stimulant effects of cocaine were enhanced in a within-subjects dose-response experiment. However, further study revealed that in mice injected with 20 mg/kg for the first time, there was no difference in the locomotor-stimulating effects of cocaine between knockout and wild-type mice. In a sensitization study (modeled after the conditions in the dose-response experiment) although not observed in WT mice, OPRM1-/- mice did exhibit cocaine sensitization. By stark contrast, and similar to the effects of other rewarding drugs in OPRM1 KO mice, cocaine reward, as assessed by conditioned place preference, was reduced in both homozygous and heterozygous OPRM1 KO mice. The present results confirm a central role of the mu-opioid receptor in drug reward but opposing effects on locomotor sensitization. The reduced cocaine reward identified in heterozygous mu-opioid receptor knockout mice supports the possibility that humans with fewer available mu-opioid receptors might experience less cocaine reward.