Our goal was to identify the risk factors for co-colonization by KPC-producing Klebsiella pneumoniae (KPC-Kp), vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) upon intensive care unit (ICU) admission and during stay. Rectal and nasal samples were taken from each patient upon admission at two Greek ICUs and each week afterwards, and were inoculated onto chromogenic agar. Representative colonies were characterized with standard methods and Vitek-2 technology. The presence of the bla KPC gene (K. pneumoniae isolates), vanA and vanB (Enterococcus faecium and E. faecalis isolates), and mecA (S. aureus isolates) was confirmed by polymerase chain reaction (PCR). Upon ICU admission, among 481 patients, 59 (12%), 63 (13%), and 20 (4%) were colonized by KPC-Kp, VRE, or MRSA, respectively. Simultaneous colonization by KPC-Kp and VRE upon admission (34 patients) was associated with the number of co-morbidities [adjusted odds ratio (aOR): 1.5; confidence interval (CI) 1.0-2.5], administered antibiotics (aOR: 1.7; CI 1.3-2.3), and prior KPC-Kp infection (aOR: 24.4; CI 1.5-396.0). Among patients with an ICU stay of more than 6 days, 181 (73%), 31 (13%), and 9 (4%) became KPC-Kp, VRE, or MRSA colonized during ICU stay, respectively. KPC-Kp colonization was an independent risk factor for VRE colonization upon admission (aOR: 2.7; CI 1.0-7.2) and during stay (aOR: 7.4; CI 2.0-27.4), whereas VRE colonization was a risk factor for KPC-Kp upon admission (aOR: 5.1; CI 1.9-13.9) and MRSA colonization upon admission (aOR: 3.5; CI 1.2-10.1) and during ICU stay (aOR: 14.5; CI 2.1-100.1). Colonization by a multidrug pathogen could promote colonization by another.