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Labor initiates one of the most intensely painful episodes in a woman’s life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. μ-Opioid receptor (μOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED₅₀) of intrathecal fentanyl via combined spinal–epidural for labor analgesia. Nulliparous women were prospectively recruited around 35 weeks gestation (n=224), and genotyped for 304A/G polymorphism. Those requesting neuraxial labor analgesia were enrolled in one of the two double-blinded trials: up-down sequential allocation (SA, n=50) and a separate confirmatory random-dose allocation trial (RA, n=97). Effective analgesia from intrathecal fentanyl was defined by ⩾60min analgesia with verbal rating score ⩽1 (scale 0–10) and was compared …