Large individual differences in the clinical response to morphine therapy have been known for a long time by clinicians. The recent advances in genomic research encourage the search for pharmacogenetic causes of that variability. As a measure of central opioid effects, pupil diameters were assessed every 20 min for 18 h after administration of morphine or its active metabolite morphine-6-glucuronide (M6G) in a two-way crossover study. The opioid effects were compared between six subjects with a single-nucleotide polymorphism (SNP) A118G in the μ-opioid receptor gene (five heterozygous, one homozygous) and six control subjects. Non-parametric pharmacokinetic-pharmacodynamic modelling was employed to identify the influence of the A118G SNP on the concentration–response relationship of M6G and morphine, which was described by a sigmoidEmaxmodel. As a measure of potency, the EC50of the pupil constrictory effects of M6G was 714±197 nmol/l in wild-type and 1475±424 nmol/l in heterozygous carriers of the A118G SNP. In the homozygous carrier of the SNP, it had an EC50of 3140 nmol/l. In addition, the dose–response relationship was flatter in the A118G carriers than in control subjects (shape factor of the sigmoidEmaxmodel: γ = 3.3±1.2, 1.7±0.5 and 1.6 for wild-type, heterozygous and the homozygous A118G carriers, respectively). In contrast, the concentration–response relationship of morphine was not affected by this specific SNP. The A118G SNP in the μ-receptor gene significantly reduces the potency of M6G in humans.