Background A high prevalence of hepatitis C (HCV) in the Egyptian Nile Delta increases the demand for upper-GI endoscopy (UGIE) and the risk of cross-infection with this virus. Objective To assess the potential for UGIE to transmit HCV when endoscopes are reprocessed according to current international standards. Design A prospective cohort study to detect the incidence of HCV and hepatitis B cross-infections. Setting The endoscopic unit of the National Liver Institute, a hospital for patients with chronic liver disease. Patients A total of 859, including 149 of 249 patients (60%) at risk (HCV-antibody negative) retested 3 to 10 months after UGIE with endoscopes previously used on HCV carriers. Interventions Nurses were trained to process endoscopes according to American Society for Gastrointestinal Endoscopy guidelines, and procedures were observed and recorded. Main Outcome Measurements Seroconversions were determined by using enzyme immunoassays for anti-HCV; reverse transcriptase–polymerase chain reaction was used to detect HCV–ribonucleic acid (RNA). Results Four patients, initially negative, tested positive for anti-HCV after UGIE. However, 2 of these had HCV-RNA in their baseline blood sample, and the other 2 did not have HCV-RNA in their follow-up sample. Limitations Very-high prevalence of anti-HCV in subjects reduced the proportion at risk of infection, and follow-up was difficult. Conclusions There were no cases of proven transmission of HCV when endoscopes were reprocessed by using currently accepted standards. This negative study is encouraging, because patients undergoing UGIE in the Nile Delta of Egypt where HCV-caused liver disease is so pervasive would be at maximum risk of HCV cross-infection from UGIE.