OBJECTIVE To identify modifiable risk factors for acquisition of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae (KPC) colonization among long-term acute-care hospital (LTACH) patients. DESIGN Multicenter, matched case-control study. SETTING Four LTACHs in Chicago, Illinois. PARTICIPANTS Each case patient included in this study had a KPC-negative rectal surveillance culture on admission followed by a KPC-positive surveillance culture later in the hospital stay. Each matched control patient had a KPC-negative rectal surveillance culture on admission and no KPC isolated during the hospital stay. RESULTS From June 2012 to June 2013, 2,575 patients were admitted to 4 LTACHs; 217 of 2,144 KPC-negative patients (10.1%) acquired KPC. In total, 100 of these patients were selected at random and matched to 100 controls by LTACH facility, admission date, and censored length of stay. Acquisitions occurred a median of 16.5 days after admission. On multivariate analysis, we found that exposure to higher colonization pressure (OR, 1.02; 95% CI, 1.01-1.04; P=.002), exposure to a carbapenem (OR, 2.25; 95% CI, 1.06-4.77; P=.04), and higher Charlson comorbidity index (OR, 1.14; 95% CI, 1.01-1.29; P=.04) were independent risk factors for KPC acquisition; the odds of KPC acquisition increased by 2% for each 1% increase in colonization pressure. CONCLUSIONS Higher colonization pressure, exposure to carbapenems, and a higher Charlson comorbidity index independently increased the odds of KPC acquisition among LTACH patients. Reducing colonization pressure (through separation of KPC-positive patients from KPC-negative patients using strict cohorts or private rooms) and reducing carbapenem exposure may prevent KPC cross transmission in this high-risk patient population. Infect Control Hosp Epidemiol 2017;38:670-677.