We carried out a double-blinded, randomized prospective study to compare patient tolerance of small diameter endoscopes using limited potency oral premedication to complement topical anesthesia. Patients randomly received either oral placebo, diphenhydramine (100 mg), acetaminophen (1000 mg), or both drugs 30 to 60 min prior to endoscopy. All patients received topical Cetacaine and underwent upper endoscopy with the Olympus XP10 7.9-mm fiberscope. The combination of acetaminophen (1000 mg) and diphenhydramine (100 mg) significantly improved tolerance over topical anesthetic alone. Obvious sedation from the medications was infrequent. Gag response after a topical anesthesia was a significant predictor of patient tolerance. We conclude that small diameter endoscopes are well tolerated for diagnostic upper endoscopy. Oral premedications additionally improve tolerance slightly.