OBJECTIVE: To determine the occurrence of co-colonization or co-infection with VRE and MRSA among medical patients requiring intensive care. DESIGN: Prospective, single-center, observational study. SETTING: A 19-bed medical ICU in an urban teaching hospital. PATIENTS: Adult patients requiring at least 48 hours of intensive care and having at least one culture performed for microbiologic evaluation. RESULTS: Eight hundred seventy-eight consecutive patients were evaluated. Of these patients, 402 (45.8%) did not have microbiologic evidence of colonization or infection with either VRE or MRSA, 355 (40.4%) were colonized or infected with VRE, 38 (4.3%) were colonized or infected with MRSA, and 83 (9.5%) had co-colonization or co-infection with VRE and MRSA. Multiple logistic regression analysis demonstrated that increasing age, hospitalization during the preceding 6 months, and admission to a long-term-care facility were independently associated with colonization or infection due to VRE and co-colonization or co-infection with VRE and MRSA. The distributions of positive culture sites for VRE (stool, 86.7%; blood, 6.5%; urine, 4.8%; soft tissue or wound, 2.0%) and for MRSA (respiratory secretions, 34.1%; blood, 32.6%; urine, 17.1%; soft tissue or wound, 16.2%) were statistically different (P < .001). CONCLUSIONS: Co-colonization or co-infection with VRE and MRSA is common among medical patients requiring intensive care. The recent emergence of vancomycin-resistant Staphylococcus aureus and the presence of a patient population co-colonized or co-infected with VRE and MRSA support the need for aggressive infection control measures in the ICU (Infect Control Hosp Epidemiol 2004;25:99-104).