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Medical comorbidities such as renal, cardiac, and cerebrovascular disease are known risk factors for mortality in burn patients. Patients with large burns often require blood transfusions during excision and skin grafting. The purpose of this study was to determine if there was a difference in the transfusion requirements of burn patients with/without comorbidities. This was a retrospective review of burn patient data between March 1999 and May 2004. There were 1,615 admissions to the burn unit; comorbidity data was available on 1,490 patients. Of these, 383/1,490 (26%) had comorbid conditions upon admission: 85/383 (22%) were transfused; 52/85 (61%) also underwent skin grafting. Most patients (298/383) with comorbidities were not transfused; however, 108/298 (36%) were grafted. Transfused patients with comorbidities had a mean ± SD age of 53 ± 18 years old, a 19% ± 22% TBSA burn, and a length of stay of 29 ± 26 days compared with patients with comorbidities who did not require transfusion and were 48 ± 19 years old, had 8 ± 13% TBSA, and a length of stay of 8 ± 8 days. Of patients with comorbidities, 31/54 (57%) were transfused in the <10% TBSA group and 26/44 (59%) in the 10 to 19% TBSA group. There was a 5-fold increase in mortality among the transfused patients with comorbidities compared with the nontransfused group. Patients with comorbidities were more likely to be transfused in the <20% TBSA patient group. The odds of receiving a transfusion were highest in patients with cardiac diseases, stroke, and other central nervous system and psychiatric disorders. Co-occurring conditions that increased the odds of receiving a transfusion were procedures and inhalation with burn injury.