The three opioid receptor genes, and in particular the mu and delta loci (OPRM1 and OPRD1, respectively), are compelling candidates to influence risk for substance dependence. Previous study of a variant at the OPRD1 locus, T921C, has shown association with opioid dependence. This variant does not alter protein sequence, and could not be directly responsible for a physiologic effect. We sequenced the OPRD1 coding region in six individuals with differing T921C alleles, to identify new common variants more likely to explain the association with phenotype. We identified one novel variant in exon 1, 80T-->G, which predicts a change in amino acid sequence from phenylalanine (80T) to cysteine (80G) (F27C). We present here basic population genetics of this variant, and population genetic data for the T921C variant. We found significant differences in allele frequency between populations, and a maximum frequency of the 80G allele of 9%, in each of two European populations. This variant could contribute to the previously reported association results.