The purpose of this study was to prospectively compare the effectiveness of three different gut decontamination methods in 51 patients presenting to an emergency department with tricyclic antidepressant overdose. Patients were randomized to three treatments; Group 1 received activated charcoal, Group 2 received saline lavage followed by activated charcoal, and Group 3 received activated charcoal followed by saline lavage followed by activated charcoal. Baseline characteristics of the three groups did not differ, including Glasgow Coma Scores, age, and mean tricyclic antidepressant levels. Average length of stay in admitted patients was 93.3 hours in Group 1, 107.2 hours in Group 2, and 66.7 hours in Group 3. Of those admitted to an ICU, average ICU time was 66.9 hours in Group 1, 54.1 hours in Group 2, and 34.4 hours in Group 3. Average duration of sinus tachycardia was 20.8 hours in Group 1, 30.8 hours in Group 2, and 32.2 hours in Group 3. Of those requiring mechanical ventilation, average ventilator time was 43.4 hours in Group 1, 24.1 hours in Group 2, and 17.8 hours in Group 3. No statistically significant difference could be shown with respect to the clinical endpoints noted. There were no deaths in any of the groups. All three methods of gut decontamination had similar clinical outcomes.