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Background and Objective Open-access endoscopy allows physicians to directly schedule endoscopic procedures for their patients without prior consultation. An evaluation of both appropriateness and diagnostic yield of endoscopic procedures is critical when assessing the costs and benefits of endoscopy in an open-access setting. The aim of this Italian multicenter study was to assess the appropriate use of upper endoscopy (EGD) in an open-access system and to establish the yield of diagnostic information relevant to patient care. Design and Setting Cross-sectional, prospective, multicenter study. Patients A total of 6270 patients referred to 44 Italian centers for open-access EGD during 1 month were prospectively enrolled. Interventions The American Society for Gastrointestinal Endoscopy (ASGE) guidelines were used to assess the relation between the appropriate use of EGD and the presence of relevant endoscopic findings. Main Outcome Measurements and Results The rate for “generally not indicated” EGDs was 22.9%: 29.4% for primary care physicians and 12.9% for specialists ( P < .01). A relevant endoscopic finding was detected in 2929 examinations (46.7%). The diagnostic yield was significantly higher for “generally indicated” EGDs compared with “generally not indicated” procedures (52% vs 29%; odds ratio [OR] 2.65, 99% confidence interval [CI] 2.23-3.20; P < .01). Of the 133 malignant lesions diagnosed, all but 1 were diagnosed in patients with an appropriate indication (OR >20, 99% CI 3 to >100; P < .01). Conclusions Open-access EGD is an useful procedure for clinical practice. Because most of the relevant findings were detected during examinations performed for appropriate indications, the use of ASGE guidelines emerges as crucial to the cost-effectiveness of an open-access system.