Background MRSA colonization is a common neonatal problem and is associated with invasive infection. Good hand-washing and contact precautions reduce transmission. However, long-term contact isolation, sometimes for months, causes dissatisfaction among neonatal intensive care unit (NICU) care providers and parents. We examined the effectiveness of MRSA decolonization among neonates over 3 years. Methods Our NICU patients are routinely screened for MRSA colonization by PCR testing of nasal and rectal swabs upon admission and every 2 weeks. Patients with a history of MRSA infection or colonization became eligible for MRSA eradication upon reaching 2000g. Our protocol included intranasal muporocin 2% ointment applied to both nares twice daily for 5 days and 2% chlorhexidine wipe bath daily for 7 days. Wipes were used for bathing from the neck down for at least 20 sec per wipe. Two wipes were used for patient’s < 10 kg with the first wipe being used on the neck, chest, arms, and back, and the second wipe being used on the legs, buttocks, and perineum. Patients were excluded from chlorhexidine bathing if they had a known allergy, were < 27 weeks gestation, < 1 week chronological age, receiving phototherapy, or had severe skin disease, open wounds, or burns. Contact isolation was discontinued if 2 sets of nares and rectal PCR swabs 5 days apart were negative and the patient had not been on antibiotics during the screening period. Surveillance MRSA PCR testing continued. Contact isolation was to be re-initiated if subsequent MRSA screening was positive. Patients were not decolonized a second time. Results Among infants admitted to the NICU during from 2016 to 2018 MRSA colonization was identified in 102 patients. Fifty-six were noted to have colonization present on admission and 46 were acquired on or after hospital day 3. The decolonization protocol with follow-up screening was completed in 33 infants. Successful decolonization was achieved for only 5 (15%) of infants. There were no adverse reactions noted among neonates and no MRSA decolonized patients reverted to positive by PCR screening while in hospital. Conclusion 85% of neonates with MRSA failed decolonization. Using mupirocin intranasally and chlorhexidine bathing to decolonize neonates with MRSA was welcomed by staff and families, but was poorly effective. Disclosures All authors: No reported disclosures.