The incidence of hospital-associated infections secondary to methicillin-resistant Staphylococcus aureus (MRSA) and those caused by vancomycin-resistant enterococci (VRE) continue to increase, despite the publication of evidence-based guidelines on infection control. We sought to determine modifiable risks factors for acquisition of MRSA or VRE or both on a burn trauma unit (BTU). We performed a retrospective single-center-matched control study. Our study group comprised 94 patients who acquired MRSA or VRE or both while on the BTU from January 1, 2001 to December 31, 2005. The case-patients were matched 1:1 to control-patients based on the time the cases were exposed to the BTU before they became colonized or infected. Logistic regression was used to analyze the relationship of demographic, procedure, and antimicrobial exposure variables to acquisition of MRSA or VRE. Acquisition of MRSA or VRE was related to patient factors, antimicrobial exposure, and device use. Younger age and prior vancomycin treatment while on the BTU were independently associated with MRSA acquisition. The presence of a Foley catheter was related to VRE acquisition. Sixteen study patients (17.0%) who became colonized on the BTU subsequently acquired 17 infections: six patients had MRSA bloodstream infections, nine had MRSA burn wound infections, and two had VRE urinary tract infections. Younger age, exposure to vancomycin, or Foley catheters were associated with increased risk of acquiring MRSA or VRE. Protocols or algorithms that help physicians remember to assess the necessity of antimicrobial agents and devices may help limit the duration of exposure to these risk factors, which may enhance infection prevention efforts. Future studies need to explore the effect of these variables on cross-transmission and their impact predominately in a burn unit.