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Introduction Chagas disease (CD) remains a major cause of cardiac and digestive morbidity and premature death in the Americas. Although benznidazole (BZN) and nifurtimox (NFX) are the only two available trypanocidal agents worldwide, direct comparisons between these two drugs in Brazilian adults are lacking. Therapeutic efficacy in chronically infected adults remains unclear as parasitological response is variable and serological negativisation is not frequent within short-term follow-up. Furthermore, the genetic diversity of Trypanosoma cruzi may influence treatment response and has been largely overlooked in clinical studies. The BENBRASIL trial aims to compare the efficacy and safety of BZN versus NFX in adults with chronic CD and to explore geographical variation in response to standard BZN treatment.Methods and analysis The BENBRASIL trial is a multicentre, randomised, double-blind, double-dummy phase II superiority trial conducted in Brazil alongside a prospective observational cohort.A total of 150 adults with chronic indeterminate or mild cardiac forms of CD will be randomly allocated in a 1:1 ratio to receive standard BZN dose or NFX for 8 weeks in a double-blind, double-dummy placebo-controlled design and will be followed for 12 months. The primary endpoint is therapeutic efficacy defined as sustained parasitological response in PCR for parasitic DNA results for 12 months follow-up. Treatment failure will be defined as one confirmed PCR positivity, treatment discontinuation due to toxicity or death related to CD. Secondary outcomes include drug tolerability (including graded adverse events), treatment adherence and serological titres. The sample size (75 participants per arm) was calculated to provide approximately 80–85% power to detect a 25% absolute difference in sustained PCR negativity between groups at a two-sided α of 0.05. Additionally, a prospective observational cohort will enrol 300 additional participants receiving standard treatment of BZN to evaluate the effectiveness and safety of BZN across five epidemiological and geographical regions of Brazil representing distinct parasite genetic backgrounds. It aims to explore geographical variation in parasitological response within different discrete typing units using mixed-effects regression models adjusted for baseline covariates. The primary analysis will follow the intention-to-treat principle. For the primary endpoint, missing outcome data will be conservatively classified as treatment failure, with sensitivity analyses using multiple imputations. Recruitment began in March 2024.Ethics and dissemination The protocol has been approved by Brazil’s National Research Ethics Committee and the institutional review boards of all participating centres. Written informed consent will be obtained from all participants. An independent Data Safety Monitoring Board will oversee safety outcomes. Study findings will be disseminated through peer-reviewed publications, scientific conferences and communication with national health authorities. Results may guide clinical practice and regulatory policies, strengthening therapeutic options for CD.Trial registration number ReBEC U1111-1287-7587. Date of registration: 06/07/2023 ( https://ensaiosclinicos.gov.br/rg/RBR-973pt5n).