AIM: Chagas disease (ChD) is a neglected disease affecting approximately 7 million individuals in Latin America. Benznidazole (BZ) is the most commonly used treatment. Therefore, understanding the adverse effects of BZ is crucial for devising targeted monitoring and interventions to enhance patient management. METHODS: A retrospective cohort study of patients with ChD treated with BZ to identify and characterize BZ adverse drug reactions (ADRs). RESULTS: 518 patients were enrolled: 449 children (median age: 4yrs, range 1mo-17.75yrs) and 69 adults (median age: 25yrs, range 18-59). A 75% of pediatric patients received a median dose of BZ of 6.6 mg/kg/day (IQR25–75 = 5.7-7.3) for at least 60 days. Adult patients received a median BZ dose of 5.6 mg/kg/day (IQR25–75 = 5.2-6.1) for a median duration of 31 days (IQR25–75 = 30-60). Overall, 152/518 (29.34%) patients developed BZ-related ADRs, with an incidence of 116/449 (25.83%) in children and 36/69 (52.17%) in adults (OR = 0.32, CI95 = 0.19 to 0.54, p < 0.001). The study identified 240 ADRs, primarily mild to moderate, but severe ADRs occurred in 1.11% of children and 1.45% of adults. The skin was the most affected system in both groups. A 10.23% of patients abandoned treatment (53/518). Adults discontinued treatment more frequently than children (OR = 3.36 CI95 = 1.7 to 6.4, p < 0.001). CONCLUSION: Our study supports the safety of BZ for ChD in children and adults. Avoiding BZ treatment due to safety concerns does not seem to be supported by the evidence.