Individual differences in sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. Still controversial is whether the single nucleotide polymorphisms (SNPs) of the human OPRM1 gene encoding the mu-opioid receptor influence the analgesic effects of opioids. We examined associations between fentanyl sensitivity and the two SNPs, A118G and IVS3+A8449G, in the human OPRM1 gene in 280 Japanese patients undergoing painful orofacial cosmetic surgery, including bone dissection. Regarding the A118G SNP in exon 1, in a cold pressor-induced pain test before surgery, less analgesic effects of fentanyl were shown in subjects carrying the minor G allele of the A118G SNP (median of difference between pain perception latencies before and after fentanyl injection [PPLpost-PPLpre]: 12s) compared with subjects not carrying this allele (PPLpost-PPLpre: 15s, p=0.046). Furthermore, the IVS3+A8449G SNP in intron 3, which represents a complete linkage disequilibrium block with more than 30 SNPs from intron 3 to the 3' untranslated region, was associated with 24-h postoperative fentanyl requirements. Subjects carrying the minor G allele of the IVS3+A8449G SNP required significantly less fentanyl for 24-h postoperative pain control (median: 1.5microg/kg) compared with subjects not carrying this allele (median: 2.5microg/kg, p=0.010). Although further validation is needed, the present findings shed light on the involvement of OPRM1 3' untranslated region polymorphisms in fentanyl sensitivity in addition to the A118G SNP and open new avenues for personalized pain treatment with fentanyl.