Objective-To compare hydromorphone with oxymorphone, with or without acepromazine, for preanesthetic sedation in dogs and assess changes in plasma concentration of histamine after drug administration. Design-Randomized clinical study. Animals-10 healthy mixed-breed dogs. Procedure-Dogs were treated IM with hydromorphone (group H), oxymorphone (group O), hydromorphone with acepromazine (group H/A), or oxymorphone with acepromazine (group O/A). Sedation score, heart rate, respiratory rate, systolic blood pressure, and oxygen saturation were recorded at baseline immediately after drug administration (T0) and every 5 minutes for 25 minutes (T25). Plasma histamine concentration was measured at baseline and T25. Results-Sedation was similar between groups H and O at all times. Sedation was significantly greater for groups H/A and O/A from T10 to T25, compared with other groups. Systolic blood pressure was significantly reduced at T25 in group H/A, compared with group H, and in group O/A, compared with group O. Prevalence of panting at T25 was 50% for groups H and O, compared with 20% for group H/A and 30% for group O/A. By T25, heart rate was significantly lower in all groups. Oxygen saturation was unaffected by treatment. Mean +/- SD plasma histamine concentration was 1.72 +/- 2.69 ng/ml at baseline and 1.13 +/- 1.18 ng/ml at T25. There was no significant change in plasma histamine concentration in any group. Conclusions and Clinical Relevance-Hydromorphone is comparable to oxymorphone for preanesthetic sedation in dogs. Sedation is enhanced by acepromazine. Neither hydromorphone nor oxymorphone caused an increase in plasma histamine concentration.