BACKGROUND. Staphylococcus aureus is an important cause of infection in intensive care unit (ICU) patients. Colonization with methicillinresistant S. aureus (MRSA) is a risk factor for subsequent S. aureus infection. However, MRSA-colonized patients may have more comorbidities than methicillin-susceptible S. aureus (MSSA)-colonized or noncolonized patients and therefore may be more susceptible to infection on that basis. OBJECTIVE. To determine whether MRSA-colonized patients who are admitted to medical and surgical ICUs are more likely to develop any S. aureus infection in the ICU, compared with patients colonized with MSSA or not colonized with S. aureus, independent of predisposing patient risk factors. DESIGN. Prospective cohort study. SETTING. A 24-bed surgical ICU and a 19-bed medical ICU of a 1,252-bed, academic hospital. PATIENTS. A total of 9,523 patients for whom nasal swab samples were cultured for S. aureus at ICU admission during the period from December 2002 through August 2007. METHODS. Patients in the ICU for more than 48 hours were examined for an ICU-acquired S. aureus infection, defined as development of S. aureus infection more than 48 hours after ICU admission. RESULTS. S. aureus colonization was present at admission for 1,433 (27.8%) of 5,161 patients (674 [47.0%] with MRSA and 759 [53.0%] with MSSA). An ICU-acquired S. aureus infection developed in 113 (2.19%) patients, of whom 75 (66.4%) had an infection due to MRSA. Risk factors associated with an ICU-acquired S. aureus infection included MRSA colonization at admission (adjusted hazard ratio, 4.70 [95% confidence interval, 3.07-7.21]) and MSSA colonization at admission (adjusted hazard ratio, 2.47 [95% confidence interval, 1.52-4.01]). CONCLUSION. ICU patients colonized with S. aureus were at greater risk of developing a S. aureus infection in the ICU. Even after adjusting for patient-specific risk factors, MRSA-colonized patients were more likely to develop S. aureus infection, compared with MSSAcolonized or noncolonized patients.