Background: The prescription of methadone in advanced cancer poses multiple challenges due to the considerable interpatient variation seen in effective dose and toxicity. Previous reports have suggested that ARRB2 influences the response to methadone in opioid substitution therapy. Associations with opioid response for pain management in advanced cancer are conflicting, with no studies including methadone as the primary intervention. Methods: In a prospective, multicenter, open-label dose-individualization study, we investigated whether polymorphisms in ARRB2 were associated with methadone dose requirements and pain severity. Results: Significant associations were found for rs3786047, rs1045280, rs2036657 and pain score. Conclusion: While studies are few and the sample size small, ARRB2 genotyping may assist in individualized management of the most feared symptom in advanced cancer.