ObjectiveTo assess depth and quality of sedation and the ability to place an intravenous catheter in cats after intramuscular (IM) injection with alfaxalone–methadone–midazolam (AMM) or ketamine–methadone–midazolam (KMM). Study designBlinded randomized clinical trial. AnimalsA group of 46 healthy Domestic Short Hair cats. MethodsCats were randomly assigned to be administered IM methadone 0.3 mg kg–1 and midazolam 0.3 mg kg–1 with either alfaxalone 2 mg kg–1 (AMM group, n = 23) or ketamine 3 mg kg–1 (KMM group, n = 23). Before IM injection, a temperament score was assigned. The reaction to injection was scored. After 15 minutes, the depth of sedation was scored using a simple descriptive scale (SDS) and multidimensional sedation score. Success or failure to place an intravenous catheter at first attempt was recorded; p < 0.05. ResultsCats in the AMM group had a significantly higher median temperament score (p = 0.026). Behavioural reaction to injection with AMM was significantly less compared with KMM (p = 0.016). Median sedation scores were significantly higher in the AMM group than in the KMM group: SDS 4 (0–4) versus 2 (0–4), p = 0.01, respectively; multidimensional sedation score AMM 13 (0–13) versus 3 (0–10), indicating superior sedative effect in the AMM group, p = 0.01. Success rate of catheter placement was significantly higher in the AMM group (18/23) than in the KMM group (10/23), p = 0.033. Conclusionsand clinical relevance Addition of 2 mg kg–1 alfaxalone to 0.3 mg kg–1 methadone and 0.3 mg kg–1 midazolam provided better sedation after IM injection than ketamine 3 mg kg–1 combined with the same doses of methadone and midazolam. This combination of drugs may be particularly desirable as an alternative to α-2 adrenoceptor agonist-based protocols for cats requiring IM sedation.