Objective-To compare the anesthetic and cardiorespiratory effects of total IV anesthesia with propofol (P-TIVA) or a ketamine-medetomidine-propofol combination (KMP-TIVA) in horses. Design-Randomized experimental trial. Animals-12 horses. Procedure-Horses received medetomidine (0.005 mg/kg [0.002 mg/lb], IV). Anesthesia was induced with midazolam (0.04 mg/kg [0.018 mg/lb], IV) and ketamine (2.5 mg/kg [1.14 mg/lb], IV). All horses received a loading dose of propofol (0.5 mg/kg [0.23 mg/lb], IV), and 6 horses underwent P-TIVA (propofol infusion). Six horses underwent KMP-TIVA (ketamine [1 mg/kg/h {0.45 mg/lb/h}] and medetomidine [0.00125 mg/kg/h {0.0006 mg/lb/h}] infusion; the rate of propofol infusion was adjusted to maintain anesthesia). Arterial blood pressure and heart rate were monitored. Qualities of anesthetic induction, transition to TIVA, and maintenance of and recovery from anesthesia were evaluated. Results-Administration of KMP IV provided satisfactory anesthesia in horses. Compared with the P-TIVA group, the propofol infusion rate was significantly less in horses undergoing KMP-TIVA (0.14 +/- 0.02 mg/kg/min [0.064 +/- 0.009 mg/lb/min] vs 0.22 +/- 0.03 mg/kg/min [0.1 +/- 0.014 mg/lb/min]). In the KMP-TIVA and P-TIVA groups, anesthesia time was 115 +/- 17 minutes and 112 +/- 11 minutes, respectively, and heart rate and arterial blood pressure were maintained within acceptable limits. There was no significant difference in time to standing after cessation of anesthesia between groups. Recovery from KMP-TIVA and P-TIVA was considered good and satisfactory, respectively. Conclusions and Clinical Relevance-In horses, KMP-TIVA and P-TIVA provided clinically useful anesthesia; the ketamine-medetomidine infusion provided a sparing effect on propofol requirement for maintaining anesthesia.