OBJECTIVE To establish the minimum alveolar concentration (MAC) of desflurane and evaluate the effects of 2 opioids on MAC in sheep. ANIMALS 8 adult nulliparous mixed-breed sheep. PROCEDURES A randomized crossover design was used. Each sheep was evaluated individually on 2 occasions (to allow assessment of the effects of each of 2 opioids), separated by a minimum of 10 days. On each occasion, sheep were anesthetized with desflurane in 100% oxygen, MAC of desflurane was determined, oxymorphone (0.05 mg/kg) or hydromorphone (0.10 mg/kg) was administered IV, and MAC was redetermined. Physiologic variables and arterial blood gas and electrolyte concentrations were measured at baseline (before MAC determination, with end-tidal desflurane concentration maintained at 10%) and each time MAC was determined. Timing of various stages of anesthesia was recorded for both occasions. RESULTS Mean ± SEM MAC of desflurane was 8.6 ± 0.2%. Oxymorphone or hydromorphone administration resulted in significantly lower MAC (7.6 ± 0.4% and 7.9 ± 0.2%, respectively). Cardiac output at MAC determination for desflurane alone and for desflurane with opioid administration was higher than that at baseline. No difference was identified among hematologic values at any point. Effects of oxymorphone and hydromorphone on durations of various stages of anesthesia did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE MAC of desflurane in nulliparous adult sheep was established. Intravenous administration of oxymorphone or hydromorphone led to a decrease in MAC; however, the clinical importance of that decrease was minor relative to the effect in other species.