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To compare xylazine and romifidine constant rate infusion (CRI) protocols regarding degree of sedation, and effects on postural instability (PI), ataxia during motion (A) and reaction to different stimuli.Blinded randomized experimental cross-over study.Ten adult horses.Degree of sedation was assessed by head height above ground (HHAG). Effects on PI, A and reaction to visual, tactile and acoustic stimulation were assessed by numerical rating scale (NRS) and by visual analogue scale (VAS). After baseline measurements, horses were sedated by intravenous loading doses of xylazine (1 mg kg−1) or romifidine (80 μg kg−1) administered over 3 minutes, immediately followed by a CRI of xylazine (0.69 mg kg−1hour−1) or romifidine (30 μg kg−1 hour−1) which was administered for 120 minutes. Degree of sedation, PI, A and reaction to the different stimuli were measured at different time points before, during and for one hour after discontinuing drug administration. Data were analysed using two-way repeated measures anova, a Generalized Linear Model and a Wilcoxon Signed Rank Test (p < 0.05).Significant changes over time were seen for all variables. With xylazine HHAG was significantly lower 10 minutes after the loading dose, and higher at 150 and 180 minutes (i.e. after CRI cessation) compared to romifidine. Reaction to acoustic stimulation was significantly more pronounced with xylazine. Reaction to visual stimulation was greater with xylazine at 145 and 175 minutes. PI was consistently but not significantly greater with xylazine during the first 30 minutes. Reaction to touch and A did not differ between treatments. Compared to romifidine, horses were more responsive to metallic noise with xylazine.Time to maximal sedation and to recovery were longer with romifidine than with xylazine.With romifidine sufficient time should be allowed for complete sedation before manipulation.