BACKGROUND Pharmacological preconditioning of dexmedetomidine on small intestinal ischaemia/reperfusion injury has been reported in different animal models including horses. OBJECTIVE The objective was to assess if xylazine and lidocaine have a preconditioning effect in an experimental model of equine jejunal ischaemia. METHODS Terminal in vivo experiment. METHODS Ten horses under general anaesthesia were either preconditioned with xylazine (group X; n = 5) or lidocaine (group L; n = 5). A historical untreated control group (group C; n = 5) was used for comparison. An established experimental model of equine jejunal ischaemia was applied, and intestinal samples were taken pre-ischaemia, after ischaemia and following reperfusion. Histomorphological examination was performed based on a modified Chiu score. Immunohistochemical staining for cleaved caspase-3, TUNEL and calprotectin was performed, and positive cell counts were expressed in cells/mm2 . RESULTS There was no progression of histomorphological mucosal injury from ischaemia to reperfusion, and there were no differences in histomorphology between the groups. After ischaemia, group X had significantly less caspase-positive cells compared to the control group with a median difference of 227% (P = .01). After reperfusion, group X exhibited significantly lower calprotectin-positive cell counts compared to the control group, with a median difference of 6.8 cells/mm2 in the mucosa and 44 cells in the serosa (P = .02 and .05 respectively). All groups showed an increase in caspase- and calprotectin-positive cells during reperfusion (P < .05). TUNEL-positive cells increased during ischaemia, followed by a decrease after reperfusion (P < .05). CONCLUSIONS The small sample size and the use of a historical control group. Preconditioning effects of the tested drugs may be masked by the protective effects of isoflurane in the anaesthetic protocol. CONCLUSIONS Preconditioning with lidocaine did not have any effect on the tested variables. The lower cell counts of caspase- and calprotectin-positive cells in group X may indicate a beneficial effect of xylazine on ischaemia/reperfusion injury. Due to the absence of a concurrent reduction of histomorphological injury, the clinical significance remains uncertain.