BACKGROUND: Chagas disease is a neglected tropical disease. About 6 to 8 million people are chronically infected and 10% to 15% develop irreversible gastrointestinal disorders, including megaesophagus. Treatment focuses on improving symptoms, and isosorbide and nifedipine may be used for this purpose. METHODOLOGY: We conducted a systematic review to evaluate the effectiveness of pharmacological treatment for Chagas' megaesophagus. We searched MEDLINE, Embase and LILACS databases up to January 2018. We included both observational studies and RCTs evaluating the effects of isosorbide or nifedipine in adult patients with Chagas' megaesophagus. Two reviewers screened titles and abstracts, selected eligible studies and extracted data. We assessed the risk of bias using NIH 'Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group' and RoB 2.0 tool. Overall quality of evidence was assessed using GRADE. PRINCIPAL FINDINGS: We included eight studies (four crossover RCTs, four before-after studies). Three studies evaluated the effect of isosorbide on lower esophageal sphincter pressure (LESP), showing a significant reduction (mean difference -10.52mmHg, 95%CI -13.57 to-7.47, very low quality of evidence). Three studies reported the effect of isosorbide on esophageal emptying, showing a decrease in esophageal retention rates (mean difference -22.16%, 95%CI -29.94 to -14.38, low quality of evidence). In one study, patients on isosorbide reported improvement in the frequency and severity of dysphagia (moderate quality of evidence). Studies evaluating nifedipine observed a decrease in LESP but no effect on esophageal emptying (very low and low quality of evidence, respectively). Isosorbide had a higher incidence of headache as a side effect than nifedipine. CONCLUSIONS: Although limited, available evidence shows that both isosorbide and nifedipine are effective in reducing esophageal symptoms. Isosorbide appears to be more effective, and its use is supported by a larger number of studies; nifedipine, however, appears to have a better tolerability profile. TRIAL REGISTRATION: PROSPERO CRD42017055143. ClinicalTrials.gov CRD42017055143.