Introduction: The relationship between iron and infection has been investigated in Dialysis patients who are at a high risk for infection. Little is known about the relationship between serum iron status and adverse outcomes in critically ill patients. Methods: We performed a two center observational study of patients treated in medical and surgical intensive care units in Boston, Massachusetts. All data was obtained from the Research Patient Data Registry at Partners HealthCare. We studied 4,703 patients, age ≥ 18 years, who received critical care between 1997 and 2011 who had serum iron levels measured within a year prior to hospital admission. Patients with end stage renal disease prior to critical care initiation were identified by submitting the administrative data to the United States Renal Data System and excluded due to high prevalence of both intravenous iron supplementation and bloodstream infection in this population The exposure of interest was serum iron categorized a priori as 0–59.9 μg/dL, 60–169.9 μg/dL (referent) and > 170 μg/dL. The primary outcome was bloodstream infection determined by positive blood culture in the 48 hours prior to ICU admission to 48 hours after ICU admission. Secondary outcomes included sepsis and 30-day mortality. Sepsis was defined by ICD-9-CM and validated by the 2001 SCCM/ESICM, ACCP, ATS, SIS international sepsis definitions conference guidelines. Information on vital status for the study cohort was obtained from the Social Security Administration Death Master File which has high sensitivity and specificity for mortality. Adjusted odds ratios were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both serum iron and bloodstream infection. Adjustment included age, race, gender, comorbidities (Deyo-Charlson Index) and patient type (medical versus surgical). Results: The majority of patients were men (55%), white (78%) and had medical related DRGs (71%). The mean (SD) age at ICU admission was 63.9 (16.1) years. 243 (5%) patients had pre-hospital iron levels > 170 μg/dL. The cohort bloodstream infection rate was 18.4%, with 35.2% of patients diagnosed with sepsis, and an all cause 30-day mortality rate of 23.5%. Pre-hospital serum iron was a robust predictor of bloodstream infection and remained so following multivariable adjustment. Patients with pre-hospital serum iron > 170 μg/dL have an OR for bloodstream infection of 1.38 (95%CI, 1.00, 1.92, p=0.050) and an adjusted OR of 1.41 (95%CI, 1.01, 1.97, p=0.041) relative to patients with serum iron 60–169.9 μg/dL. Pre-hospital serum iron 0–59.9 μg/dL was not associated with increased odds of bloodstream infection relative to patients with serum iron 60–169.9 μg/dL. Further, patients with pre-hospital serum iron > 170 μg/dL have an OR for sepsis of 1.39 (95%CI, 1.05, 1.84, p=0.022) following adjustment for age, gender, race, patient type and Deyo-Charson index, relative to patients with serum iron 60–169.9 μg/dL. Patients with pre-hospital serum iron > 170 μg/dL have an OR for 30-day mortality of OR of 1.42 (95%CI, 1.02, 1.96, p=0.035) following adjustment for age, gender, race, patient type, Deyo-Charson index and acute organ failure, relative to patients with serum iron 60–169.9 μg/dL. Conclusions: In critically ill patients, an elevated serum iron >170 μg/dL prior to hospitalization is a robust predictor of the development of bloodstream infection, sepsis and 30-day mortality following ICU admission. If our findings are corroborated, information regarding iron metabolism and its relationship to infection in the critically ill may potentially help guide infection management efforts in the ICU.