Hypermetabolic and catabolic states in large TBSA burns lead to higher basal body temperature and tachycardia. These metabolic changes complicate the diagnosis of bacteremia and sepsis. Current indications for obtaining blood cultures (BCs) in this population are poorly described and nonstandardized. Fever, leukocytosis, and lactic acidosis are common during sepsis. This study aims to identify limits of these parameters with the highest rates of bacteremia. A retrospective review was performed for burn patients with > 20% TBSA between January 2009 and June 2011. BCs were collected with corresponding body temperature, white blood cell (WBC) count, and serum lactate levels. Positive culture rates were analyzed with univariate and multivariate analysis. Seventy-one patients met inclusion criteria and 360 BCs were included in data analysis. Cultures taken with temperature > 38.9°C were significantly more positive (P = .01) than temperatures between 38 and 38.9°C. There were significantly more positive cultures when the WBC count was < 4.5 compared with those ≥ 4.5 × 103/µl (P = .04). Lactate was an independent predictor of bacteremia (OR, 1.81; 95% CI, 1.21–12.71). Cultures were significantly more positive when the lactate level was ≥ 2.5 compared with < 2.5 mg/dL (P = .02). A temperature ≥ 38.5°C and a lactate ≥ 2.5 mg/dL corresponded to a 28.6% positive culture rate compared with 4.8% for all other scenarios (P = .001). This study demonstrates that body temperature > 38.9°C, WBC < 4.5 × 103/µl, and serum lactate ≥ 2.5 mg/dL have the highest rate for positive BCs in severe burn patients. A combination of leukopenia and pyrexia as well as lactic acidosis and pyrexia represent even higher specificity for positive BC in these patients.