Tricyclic antidepressant (TCA) poisoning is a major problem in medicine, with a high morbidity and mortality rate. The main cause of fatality is cardiac arrhythmias resulting from intoxication. Sodium bicarbonate is the drug of choice, but severe poisoning necessitates further interventions. Magnesium sulfate seems to be effective in this condition. In a randomized, clinical trial, we evaluated all patients with a history of TCA intoxication referred to the Loghman Hakim Hospital Poison Center. The patients were randomly divided into two groups: one treated by bicarbonate infusion (control group) and the other (case group) by the infusion of magnesium sulfate in addition to the treatment in the first group. Seventy-two patients were recruited into the study (36 cases and 36 controls). Mean duration of intensive care unit stay in the cases and controls were 25.63 ± 9.33 and 82.67 ± 21.66 hours, respectively (P < 0.001). Mortality rate in the case group was 13.9% and 33.3% in the other group (P = 0.052). Magnesium sulfate can be an effective drug in the treatment of TCA poisoning; however, several randomized, clinical trials are still necessary to confirm this.