The Single-Nucleotide-Polymorphism (SNP) 118A>G in the μ-1 Opioid Receptor gene (OPRM1) is associated with a decrease in the analgesic effects of opioids. The aim of this study is to assess whether 118A>G polymorphism could influence the analgesic response to opioid-based postoperative pain (POP) therapy. The study consisted of two parts: section α, observational, included 199 subjects undergoing scheduled surgical procedures with pain management standardized on surgery invasiveness and on expected level of postoperative pain; section β, randomized, included 41 women undergoing scheduled caesarean delivery with continuous intra-operative epidural anesthesia and post-operative analgesia (CEA). In both sections, POP was measured over 48 h (T6h-T24h-T48h) by the visual analogue scale (VAS). In section β we also tested the responsiveness of hypothalamic-pituitary-adrenal axis (HPA) expressed by Cortisol levels. In section α, with cluster analysis, subjects were analyzed according to their genotype: a group (#1) of 34 patients reporting VAS score >3 at every time lapse was identified and included only A118G carriers, while wild-type (A118A - absence of 118A>G polymorphism) patients were unevenly distributed between those with cluster #2 (VAS score <3 at every study steps) and those with cluster #3 (VAS score progressively reducing from T6h). In section (3, A118G carriers receiving epidural sufentanil had the lowest VAS scores at T24h; also in these patients, Cortisol levels remained more stable, with a mild decrease at T6h. This study shows that the OPRM1 118A>G polymorphism affects postoperative pain response in heterozygous patients: they have a different postoperative pain response than patients with wild-type genes, which may affect the efficacy of the analgesic therapy.