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IV fentanyl is used as a labor analgesic; however, few studies have reported the effects of IV fentanyl for early labor analgesia. We evaluated the analgesic response to IV fentanyl according to the combined effect of the single-nucleotide polymorphisms rs1799971 (c.118A/G, p. 40Asn/Asp) of the µ-opioid receptor gene (OPRM1) and rs4680 (c.472G/A, p.158Val/Met) of the catechol-O-methyltransferase (COMT) gene in women requesting labor analgesia.Labor analgesia was initiated with IV fentanyl 1.5 μg/kg. The primary outcome was analgesic success, defined as Numerical Verbal Pain Scale score ≤ 10/100 15 minutes after the dose of fentanyl. Analgesic and side effect outcomes were compared according to OPRM1 and COMT genotypes.One hundred six women were enrolled and received IV fentanyl. IV analgesic success was 6% in women with the combination Asn/Asn-Met/Met (n = 17) versus 20% in all other women combined (not Asn/Asn-Met/Met; P = 0.30; difference = 14%; 95% confidence interval [CI], –10% to 26%). IV analgesic success was 20% in women 118A/A (Asn/Asn) versus 21% for A/G and G/G of OPRM1 (P = 0.82; difference = 2%; 95% CI, –17% to 19%), and 10% in women 472A (Met/Met) versus 22% for A/G (Met/Val) and G/G (Val/Val) of COMT (P = 0.24; difference = 12%; 95% CI, –6% to 26%). Met/Met158 (n = 31) versus Met/Val or Val/Val of COMT was associated with a smaller decrease in Numerical Verbal Pain Scale (24 ± 18 vs 37 ± 23; P = 0.005; mean difference = –13; 99% CI, –25 to –1).This study was underpowered to draw firm conclusions on the influence of OPRM1 and COMT genotypes on labor analgesia with IV fentanyl. Further larger studies are needed to evaluate whether genotyping COMT alone or in combination with OPRM1 may have potentially useful clinical implications, such as not offering IV fentanyl in early labor to women who will most likely not benefit from it.