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As long-lived reptiles, Mojave Desert Tortoises (Gopherus agassizii (Cooper, 1861)) are expected to make substantial energetic investments in immune defense. This species also has many adaptations to living in an arid environment characterized by seasonal extremes in temperature and resource availability. By housing G. agassizii at a controlled, constant ambient temperature, we quantified predominantly temperature-independent, seasonal fluctuations in innate immune function and circulating leukocytes in a reptile. We found a decrease in bacteriocidal activity of the blood plasma in winter, with reduced function lasting into the spring. Lymphocyte numbers were elevated in fall and winter, whereas eosinophil numbers increased in summer. Thus, properties of the immune system were up- or down-regulated in different directions across the seasons. We found a much higher level of variation of leukocyte profiles among individuals than has previously been reported for other chelonians. Heterophil: lymphocyte ratios (indicative of chronic glucocorticoid levels) were not associated with any measure of immune function, and thus glucocorticoid does not seem to mediate the observed seasonal changes. We propose a new hypothesis to explain seasonal changes in immune function, based on seasonal resource limitation in the Mojave Desert, including the availability of dietary protein, energy, and opportunities for thermal regulation.