Mortality in burned patients is related to the size and depth of the burn. However, the effects of subsequent physiologic subsystem failure on mortality have not been determined. One hundred sixty-eight patients with second- and third-degree burns involving 40% or greater body surface area were analyzed to determine the relationship of subsystem failure to mortality. Cardiovascular subsystem failure was defined as the need for catecholamines for blood pressure support, pulmonary failure defined as the requirement of mechanical ventilatory assistance, renal subsystem failure defined as the need for hemodialysis, and immunologic subsystem failure defined as the presence of sepsis (fever, tachycardia, hypotension, oliguria, disorientation) and/or bactcremia. The mean age of the group was 40 ± 17 years, with 50 (30%) females and 188 (70%) males. The mean BSA burn was 59% ± 15% with an overall mortality of 58% (97 patients). Sixty-seven (40%) patients developed cardiac subsystem failure, with 100% mortality. Eighty-nine (53%) patients developed pulmonary subsystem failure, with 92% mortality. Renal subsystem failure was noted in 14 (8%) patients, with 100% mortality, and immunologic subsystem failure occurred in 96 (57%) patients, with 73% mortality. The 81 patients with multiple subsystem failure (≥2) had a significantly higher mortality (98%) than those with zero or one subsystem failure (21%) (p< 0.001). This study shows patients who develop physiologic subsystem failure following a major burn injury have an extremely high mortality rate and that multiple subsystem failure is even more devastating.