Conventional reprocessing of endoscopes with high-level disinfection is labor intensive, expensive, delays the turnover of instruments, and involves potential exposure of personnel to toxic chemicals. We report a prospective clinical trial with rigorous microbiologic assessment of a novel disposable, sterile, polyurethane sheath, which can be easily and snugly applied over a nasopharyngoscope before performing the endoscopic procedure, with enzymatic cleansing and disinfection of the instrument with 70% ethanol following the procedure to determine whether the use of the novel sheath can provide reliable protection against bacterial contamination and obviate the need for routine high-level disinfection in reprocessing. Baseline cultures were obtained at 3 time periods from the control heads and insertion shafts of nasopharyngoscopes used in 100 clinical examinations: before application of the protective sheath and execution of the procedure; immediately after the procedure and removal of the sheath; and after enzymatic cleaning, disinfection with 70% ethanol, and drying. All 100 used sheaths and 20 unused sheaths were subjected to high-pressure leak testing to assess barrier integrity. Bacteria were detected on 16 control heads and 6 shafts prior to the procedure; from 13 heads and 1 shaft immediately following the nasopharyngoscopic procedure and sterile sheath removal; and none of the instruments following cleaning, ethanol disinfection, and drying. No sheath showed loss of barrier integrity on leak testing. Use of a high-quality, snugly fitting, sterile, disposable polyurethane sheath on a nasopharyngoscope during a clinical examination, combined with enzymatic detergent cleaning and disinfection with 70% ethanol, can provide a reliably decontaminated, patient-ready instrument, eliminating the need for high-level disinfection of endoscopes.