Background: Eliminating conscious sedation for diagnostic endoscopy may be advantageous for patient safety and cost containment. The aim of this study was to identify and validate independent predictors of a comfortable, technically adequate, unsedated diagnostic upper endoscopy in Canadian patients. Methods: Patients were consecutively enrolled in a prospective fashion. Data collected on an initial cohort of 268 patients included demographics, a validated anxiety questionnaire, use of sedatives/analgesics, upper endoscopy experience, pharyngeal sensitivity, technical adequacy, and patient assessment of comfort after the procedure. The main outcome measure was “satisfactory upper endoscopy,” a composite of optimal scores for patient comfort and technical adequacy. Univariate and multivariate analyses were performed to identify the optimal predictive model of a satisfactory unsedated diagnostic upper endoscopy. Once identified, 68 additional patients were enrolled in a similar fashion from an independent prospective sample for purposes of outcome validation. Multivariate analysis was then repeated with the total cohort (N = 336). These results were then compared for concordance with those obtained from the initial cohort. Results: Among the initial 268 patients (54.3% women; mean age 51 ± 17 years), 49% were anxious, 15% regularly used sedatives and analgesics, 28% experienced increased pharyngeal sensitivity, and 41% had previously undergone upper endoscopy. Endoscopy was completed in 94.7% of patients without sedation and was technically adequate in 97%, and 80.1% were willing to repeat the procedure under similar conditions. Satisfactory upper endoscopy was achieved in only 59% of the initial cohort. The only independent and significant predictors of a satisfactory upper endoscopy were advancing age (OR 1.2: 95% CI [1.1, 1.4]) and decreased pharyngeal sensitivity (OR 0.5: 95% CI [0.27, 0.93]). Concordance of results were noted after validation with the second cohort. Satisfactory endoscopy was achieved in only 59.5% of the total cohort (n = 336); only 61% reported a comfortable procedural experience. Conclusions: The proportion of patients who can comfortably undergo technically adequate unsedated upper endoscopy is modest. Unsedated upper endoscopy is most likely to be successful under these procedural conditions in patients of advancing age with decreased pharyngeal sensitivity. The generalizability of these findings to an American population requires further study and may assist in identifying a subgroup of patients in whom it is cost-effective to perform upper endoscopy comfortably without sedation. (Gastrointest Endosc 2002;56:180-9.)