Aim: To assess association between genetic variants and opioid requirement in cancer patients. Materials & methods: A prospective observational trial of 243 advanced cancer patients with inadequate analgesia treated by the palliative care team was analyzed for ABCB1, ARRB2, COMT, GCH1, IL1RN, KCNJ6, OPRM1, RHBDF2, SCN9A and Stat6 polymorphisms. Results: For patients carrying OPRM1 118AG/GG and COMT 472GG (Val158Val) or these genotypes alone, a significant higher median percentage dose increase was observed (95.2% [32.8–345]) compared with OPRM1 118AA and COMT 472GA/AA (158Met allele carriers; 48.5% [0–98.8]; p = 0.0016). No associations were found with morphine equivalent dose after consultation palliative care team or ketamine use. Conclusion: Patients with the combined OPRM1 118AG/GG and COMT 472GG genotype required 50% higher dose increase for sufficient analgesia.