Objectives: The aim of this study was to investigate the analgesic efficacy of methadone vs buprenorphine within the QUAD protocol for anaesthesia in cats undergoing ovariohysterectomy. Methods: One hundred and twenty cats were recruited to an assessor-blinded, randomised clinical trial. Cats received either methadone (5 mg/m2) or buprenorphine (180 µg/m2) combined with ketamine, midazolam and medetomidine intramuscularly. Anaesthesia was maintained with isoflurane in oxygen. Atipamezole was administered at extubation. Pain was assessed using the feline Composite Measure Pain Scale (CMPS-F), a dynamic interactive visual analogue scale (DIVAS) and mechanical nociceptive threshold (MNT). Sedation, pain, heart rate and respiratory rate were measured prior to QUAD administration, before intubation, and 2, 4, 6 and 8 h post-QUAD administration. If indicated by the CMPS-F, rescue analgesia was provided with 0.5 mg/kg of methadone administered intramuscularly. Meloxicam was administered after the last assessment. Differences in pain scores between groups were compared using a two-way repeated-measures ANOVA and requirement for rescue analgesia was compared using a χ2 test. Results: Cats administered methadone had lower CMPS-F scores over time (P = 0.04). Eighteen of 60 cats required rescue analgesia in the methadone group vs 29/60 in the buprenorphine group (P = 0.028). All cats that received rescue analgesia required it within 6 h post-QUAD administration. There were no differences between groups in MNT or pain measured using the DIVAS. Conclusions and relevance: Methadone produced clinically superior postoperative analgesia for the first 8 h after neutering than buprenorphine when used within the QUAD protocol.