Variations in the human mu-opioid receptor gene have driven exploration of their biochemical, physiological and pathological relevance. We investigated the existence of variations in the nonhuman primate mu-opioid receptor gene to determine whether nonhuman primates can model genotype/phenotype associations of relevance to humans. Similar to the A118G single nucleotide polymorphism (SNP) in the human mu-opioid receptor gene, a SNP discovered in the rhesus monkey mu-opioid receptor gene (C77G) alters an amino acid in the N-terminal arm of the receptor (arginine for proline at position 26). Two mu-opioid receptor coding regions isolated from a single heterozygous (C77/G77) rhesus monkey brain were expressed in HEK-293 cells and characterized in radioreceptor assays. Paralleling the findings of increased affinity of beta-endorphin by the A118G allele in the human, the rhesus monkey mu-opioid receptor protein derived from the G77-containing clone demonstrated a 3.5-fold greater affinity for beta-endorphin than the receptor derived from the C77-containing clone. An assay developed to assess the incidence of the C77G SNP in a behaviorally and physiologically characterized cohort of rhesus monkeys (n=32) indicated that 44% were homozygous for C77-containing alleles, 50% were heterozygous and 6% were homozygous for G77-containing alleles. The presence of G77-containing alleles was associated with significantly lower basal and ACTH-stimulated plasma cortisol levels (P<0.03-0.05 and P<0.02, respectively) and a significantly higher aggressive threat score (P<0.05) in vivo. In a cohort of 20 monkeys, a trend towards an inverse correlation between aggressive threat and plasma cortisol levels was observed. The findings suggest that mu-opioid receptor haplotypes in monkeys can contribute to individual variability in stress response and related aggression. The data support the use of nonhuman primates to investigate mu-opioid receptor genotype/phenotype relations of relevance to humans.