gThis was an observational study comparing methicillin-resistant Staphylococcus aureus (MRSA) transmission with no decolonization of medical patients to required decolonization of all MRSA carriers during two consecutive periods: baseline with no decolonization of medical patients (16 months) and universal MRSA carrier decolonization (13 months). The setting was a one-hospital, 156-bed facility with 9,200 annual admissions. Regression models were used to compare rates of MRSA acquisition. The chi-square test was used to compare event frequencies. We used rates of MRSA clinical disease as an outcome monitor of the program. Analysis was done on 15,666 patients who had admission and discharge tests; 27.9% of inpatient days were occupied by a MRSA-positive patient (colonized patient-days) who received decolonization while hospitalized during the baseline period (this 27.9% represented those who had planned surgery) compared to 76.0% during the intervention period (P < 0.0001). The rate of MRSA transmission was 97 events (1.0%) for 9,415 admissions (2.0 transmission events/1,000 patient-days) during baseline and was 87 (1.4%) for 6,251 admissions (2.7 transmission events/1,000 patient-days) during intervention (P ؍ 0.06; rate ratio, 0.74; 95% confidence interval [CI], 0.55 to 1.00). The MRSA nosocomial clinical disease rate was 5.9 infections/10,000 patient-days in the baseline period and was 7.2 infections/10,000 patient-days for the intervention period (rate ratio, 0.82; 95% CI, 0.46 to 1.45; P ؍ 0.49). Decolonization of MRSA patients does not add benefit when contact precautions are used for patients colonized with MRSA in acute (hospital) care.