Several lines of evidence support the involvement of protein tyrosine phosphatase receptor type beta (PTPRB) in addiction. Generally, PTPs interact with both neuronal receptors and cell adhesion molecules, and appear to play roles in neurite growth and neuronal differentiation. We previously identified a role of the cell adhesion molecule NrCAM in polysubstance abuse vulnerability in humans, as well as in the rewarding effects of abused drugs in animals. Furthermore, we have identified genomic regions containing several cell adhesion molecules as polysubstance abuse vulnerability loci by whole-genome association study. The present study of human chromosome 12 loci revealed that the Ser127Gly polymorphism in PTPRB is associated with substance abuse vulnerability in three independent case-control samples (European-American from COGA families, USA, n = 177, P = 0.047; European-American from Maryland, USA, n = 650, P = 0.018; and African-American from Maryland, USA, n = 331, P = 0.009). However, this polymorphism was not associated with alcoholism in Japanese subjects (n = 1,599, P = 0.37). To confirm the importance of PTPRB in responses to drugs of abuse the expression of Ptprb in mouse brain was examined after chronic morphine treatment and found to be up-regulated in some brain regions. Thus, PTPRB is an addiction-associated and drug-regulated gene whose variants may affect substance abuse vulnerability.