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Comorbidity is a known risk factor for antibiotic-resistant bacterial infections. Although aggregate comorbidity measures are useful in epidemiologic research, none of the existing measures was developed for use with this outcome. This study compared the utility of two comorbidity measures, the Charlson Comorbidity Index and the Chronic Disease Score, in assessing the comorbidity-attributable risk of nosocomial infections with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE). Two case-control studies were conducted at the University of Maryland Medical System in Baltimore, Maryland. Cases were inpatients with a first positive clinical culture of MRSA or VRE at least 48 hours postadmission (July 1, 1998-July 1, 2001). Three inpatient controls were randomly selected per case. The MRSA study included 2,164 patients, and the VRE study included 1,948. The scores' discrimination and calibration were measured by using the c statistic and Hosmer-Lemeshow chi-square test. The Charlson Comorbidity Index (c = 0.653) and Chronic Disease Score (c = 0.608) were similar discriminators of MRSA and VRE (c = 0.670 and c = 0.647, respectively). Calibration of the scores was poor for both outcomes (p < 0.05). A revised comorbidity measure specific to resistant infections would likely provide a better assessment of the comorbidity-attributable risk of antibiotic-resistant infections.