Background. Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging multidrug-resistant nosocomial pathogen, spreading to hospitalized elderly patients. Risk factors in this setting are unclear. Our aims were to explore the contribution of multi-morbidity and disease severity in the onset of CRKP colonization/infection, and to describe changes in epidemiology after the institution of quarantine-ward managed by staff-cohorting. Methods and Findings. With a case-control design, we evaluated 133 CRKP-positive patients (75 M, 58 F; mean age 79±10 years) and a control group of 400 CRKP-negative subjects (179 M, 221 F; mean age 79±12 years) admitted to Internal Medicine and Critical Subacute Care Unit of Parma University Hospital, Italy, during a 10-month period. Information about comorbidity type and severity, expressed through Cumulative Illness Rating Scale-CIRS, was collected in each patient. During an overall 5-month period, CRKP-positive patients were managed in an isolation ward with staff cohorting. A contact-bed isolation approach was established in the other 5 months. The effects of these strategies were evaluated with a cross-sectional study design. CRKP-positive subjects had higher CIRS comorbidity index (12.0±3.6 vs 9.1±3.5, p