Background: Dexmedetomidine infusions are beneficial in anaesthetised endotoxaemic horses when administered concurrent to endotoxin, but post-conditioning effects are unknown. Objectives: To evaluate whether a dexmedetomidine infusion is beneficial in horses administered Escherichia coli O55:B5 lipopolysaccharides (LPS) endotoxin prior to anaesthesia. Study design: Randomised controlled in vivo experiment. Methods: Ten systemically healthy horses were instrumented for acquisition of cardiac index (CI) using thermodilution. All horses received IV LPS (0.1 mcg/kg bwt) prior to anesthesia. Horses received IV xylazine (control, LPS; n = 5) or dexmedetomidine (treatment, LPS-Dex; n = 5), followed by IV ketamine and midazolam and sevoflurane in oxygen. In LPS-Dex, dexmedetomidine (1.75 μg/kg bwt/hr IV) was administered and target end-tidal sevoflurane concentration was reduced (1.8% versus 3% LPS). Cardiopulmonary function, acid-base, cytokine, and creatinine values were assessed every 30 minutes for 180 minutes. Data were compared between groups using mixed model analysis (p < 0.05). Results: Mean ± standard deviation CI was significantly higher in LPS-Dex at 30 and 60 minutes (57.9 ± 15.6 mL/min/kg bwt versus 43.1 ± 9.4, 30 minutes, p = 0.03; 60.2 ± 11.8 mL/min/kg bwt versus 38.9 ± 11.2, 60 minutes, p = 0.003). Creatinine was elevated and significantly higher in LPS from 90 minutes onward but remained normal in LPS-Dex throughout (201 ± 38 μmol/L versus 124 ± 26, 180 minutes, p = 0.003). Significantly improved base excess values were seen in LPS-Dex at 150 and 180 minutes (2.9 ± 2 mmol/L versus 0.6 ± 1, 150 minutes, p = 0.03; 3.4 ± 1.96 mmol/L versus 0.6 ± 1.41, 180 minutes, p = 0.01). Cytokine concentrations were similar between groups. Main limitations: The experimental protocol is not representative of all surgical colics. Conclusions: Dexmedetomidine infusion and concurrent reduction in inhalant anesthetic could benefit anesthetic management of horses even when endotoxaemia is already present.