Desert mammals often experience scarcity of drinking water and food for prolonged periods. In this study, the first long-term acclimation experiment in a non-domesticated desert-adapted ungulate, we investigated the mechanisms used by the Arabian oryx Oryx leucoryx, to adjust its physiology to progressive food and water restriction over 5 months, an experimental regimen and time course chosen to mimic what it typically experiences between spring and late summer in the desert. At the end of the acclimation period, oryx consumed less than one and half of food and water of animals in the control group and lost 8.2±2.6% of their initial body mass. Experimental animals reduced their mass-specific resting metabolic rate (RMR) and total evaporative water loss (TEWL) by 16.2 and 25.7%, respectively, and maintained a digestive efficiency of about 70%. We found no support for the idea that reduced RMR in oryx correlated with a decreased thyroid hormone concentration in plasma. At the end of the 5 months acclimation, oryx continued to mobilize fatty acids to fuel metabolism, and did not use protein breakdown as a major source of gluconeogenesis. Oryx in the experimental group reduced their water intake by 70% and maintained constant plasma osmolality. They adjusted their water budget by reducing mass-specific TEWL, increasing urine osmolality and reducing urine volume by 40%, and excreting feces with <50% water content. Oryx have an unusually low TEWL compared with other arid-zone ungulates; both hydrated and water-deprived individuals have TEWL values, 51.7 and 39.3%, respectively, of allometric predictions for arid-zone ungulates.