We have demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. We investigated single nucleotide polymorphisms (SNPs) in the human CD38 gene in autism spectrum disorder (ASD) patients. The SNP rs3796863 (A>C) was associated with high-functioning autism (HFA) in American samples. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C>T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W;R140W) in CD38. This mutation was found in 4 probands of ASD and in family members of 3 pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. One proband with the R140W allele receiving intranasal OXT for approximately 3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods;three subjects showed improved symptoms, while 2 showed little or no effect. These results suggest that SNPs in CD38 may be risk factors for ASD by abrogating the OXT function, and that some ASD subjects can be treated with OXT in preliminary clinical trials.