The influence of cortisone in the X-irradiation syndrome was studied by making statistical comparisons of the cumulative mortality curves of groups of X-irradiated (650r whole-body) adrenalectomized CBA mice, some non-treated and others treated with intraperitoneal injections of graded doses of the hormone. The final mortality and the slope of the cumulative mortality curve of the irradiated-adrenalectomized non-hormone-treated group (i-a) were significantly greater, and the latent period between X-irradiation and onset of death shorter than those of either the hormone-treated experimental groups or the intact irradiated or adrenalectomized-non-irradiated, non-treated controls. Cortisone replacement therapy progressively restored the resistance of the i.-a. animals; as the hormone dosage was increased there was an increase in the latent periods between X-irradiation and the onset of death, and a progressive decrease in the slopes of the mortality curves. The latter were decreased to the level of the adrenalectomized but not to that of the irradiated intact controls. The greatest reduction in slope of mortality curve, per unit amount of administered hormone, was obtained with a .05 mg/day. Doses 10 and 20 times greater failed to induce any further significant reductions. The data suggest that increased mortality in the i.-a. animals was associated primarily with adrenal cortical insufficiency and that the events causing death in the irradiated-intact animals differed from those in the i.-a. groups, despite cortisone treatment. It thus seems that the adrenal cortical secretions are essential for maintaining the resistance to X-irradiation injury, and in the event of a concomitant total adrenal cortical insufficiency, cortisone may partially restore resistance.