Background: Two old drugs are the only choice against Trypanosoma cruzi and little is known about their secondary effects in the acute stage of oral-transmitted Chagas disease (ChD).Methods: A cross-sectional analytical surveillance study was conducted in a sizable cohort of patients seen during the largest acute foodborne ChD microepidemic registered so far. Individuals were treated with benznidazole (BNZ) or nifurtimox (NFX). Common Terminology Criteria for Adverse Events' was assessed to categorize side effects according to severity.Results: Out of 176 treatments applied, 79% had one or more adverse effects, which predominated in adults (97.8%) as compared to children (75.5%). Risk of side effects with NFX was significantly higher than BNZ. Four adults and a child treated with NFX had severe side effects (pulmonary infarction, facial paralysis, neutropenia, blurred vision, bone marrow hypoplasia) warranting hospitalization, and drug suspension. Adverse effects frequently reported with NFX were abdominal pain, hyporexia, weight loss, headache, nausea and lymphocytosis, whereas skin rash, neurosensory effects, hyporexia, fatigue, pyrosis, abdominal pain and eosinophilia were observed with BNZ.Conclusions: Frequency and severity of side effects during treatment of acute oral infection by T. cruzi demand direct supervision and close follow-up, even in those asymptomatic, to prevent life-threatening situations.