Combinations of a low dose of opioid, such as thiafentanil, and a high dose of medetomidine, are increasingly being used for immobilization of African ungulates. Both drugs can have undesirable cardiorespiratory effects. In this study we assessed whether vatinoxan, a peripherally acting alpha₂–adrenergic receptor antagonist, can be used to alleviate some of these effects without affecting the immobilization quality. Eight healthy, female, boma–confined blesbok (Damaliscus pygargus phillipsi), weighing a mean (SDtion) of 56.8 (4.4) kg, were immobilized twice in a randomized cross–over study with a 2–wk washout period using (1) 0.5 mg thiafentanil + 1.5 mg medetomidine (TM), (2) TM + vatinoxan: 0.5 mg thiafentanil + 1.5 mg medetomidine + 15 mg vatinoxan per milligram medetomidine (total of 22.5 mg, administered intramuscularly at 10 min post recumbency). Heart rate, respiratory rate, rectal temperature, oxygen saturation (SpO₂), arterial blood pressure, and sedation scores from 1 to 5 (1 = limited effect; 5 = excessively deep) were measured every 5 min. Arterial blood gases (PaO₂ and PaCO₂) were measured at 10, 15, 25, and 35 min postrecumbency and the alveolar––arterial oxygen gradient (P[A–a]O₂) was calculated. Induction times and immobilization quality did not differ between groups. The heart rate was significantly higher and the mean arterial pressure significantly lower in blesbok after receiving vatinoxan. All animals were hypoxemic and there were no significant differences in the respiratory rates, PaO₂, PaCO₂, SpO₂, or P(A–a)O₂ gradients at any time point. Although vatinoxan did not improve respiratory variables and blood oxygenation in these animals, the change in cardiovascular variables may suggest that it improves tissue perfusion, a positive outcome that requires further investigation.