The opioid system is involved in the action of opiate drugs, opioid addiction, pain experience and analgesia. Individual differences in opioid effect may be attributed in part to genetic variations. Long-range cis regulatory elements and intronic variants are potential sources of functional diversity. Recently, we have detected association of two intronic OPRM1 variants with heroin addiction in European Americans. In this study, we analyzed the genetic variations in the OPRM1 100 kb 5′-flanking region and intron 1 in the HapMap Caucasian population. Four major linkage disequilibrium blocks were identified, consisting of 28, 22, 15 and 42 single-nucleotide polymorphisms (SNPs), respectively. The locations of these blocks are (− 100 to− 90),(− 90 to− 67),(− 20 to− 1) and (+ 1 to+ 44) kb, respectively. The two intronic variants, indicated in our recent study, are part of a distinct haplogroup that includes SNPs from intron 1, and the proximal 5′ region. The 118G (rs1799971) allele is part of a different haplogroup that includes several variants in the distal 5′ region that may have a regulatory potential. These findings were corroborated by genotyping eight SNPs in a sample of European Americans and suggest an extended OPRM1 locus with potential new regulatory regions.