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Flexible endoscopes are exposed to blood, mucus, and other secretions during procedures. Single-use sheaths are designed to prevent contact between contaminants and reusable endoscope components. This systematic review examined findings from 22 studies that assessed endoscopic sheath use during urologic, gastrointestinal, or respiratory procedures. The evidence showed that sheaths were durable and yielded faster endoscope turnover times because their reusable components did not require high-level disinfection or sterilization. After a brief learning period, health care providers successfully assembled and maneuvered sheathed endoscopes. Patients generally did not experience greater discomfort during procedures in which sheaths were used. Microbial cultures of sheathed endoscopes were negative or similar to unsheathed endoscopes. More research is needed to evaluate the potential effect of disposable sheaths on infection risks. The evidence suggests that sheaths are a viable option for reliably providing a barrier between endoscopes and patients without affecting the quality of endoscopic procedures.