Pilot studies using a novel water method to perform screening colonoscopy allowed patients to complete colonoscopy without sedation medications and also significantly increased the cecal intubation success rate. To perform a randomized, controlled trial comparing air insufflation (conventional method) and water infusion in lieu of air insufflation (study method) colonoscopy in minimally sedated patients. Compared with the conventional method, patients examined by the study method had lower pain scores and required less medication but had a similar cecal intubation rate and willingness to undergo colonoscopy in the future. Outpatient colonoscopy in a single Veterans Affairs hospital. After informed consent and standard bowel preparation, patients received premedications administered as 0.5-increments of fentanyl (25 microg) and 0.5-increments of Versed (midazolam) (1 mg) plus 50 mg of diphenhydramine. The conventional and the study methods for colonoscopy were implemented as previously described. Additional pain medications were administered at the patients' request. Increments of medications, pain scores, cecal intubation, and willingness to repeat colonoscopy. Increments of medications used before reaching the cecum (1.6 +/- 0.2 vs 2.4 +/- 0.2, P < .0027), total increments used (1.8 +/- 0.2 vs 2.5 +/- 0.2, P < .014), and the maximum pain scores (1.3 +/- 0.3 vs 4.1 +/- 0.6, P < .0002) were significantly lower with the water method. Cecal intubation rate (100%) and willingness to undergo a repeat colonoscopy (96%) were similar. Single Veterans Affairs hospital, older male population. Water infusion in lieu of air insufflation is superior to air insufflation during colonoscopy in the minimally sedated patients (ClinicalTrials.gov Identifier NCT00785889).