ABSTRACT Infections with Trypanosoma cruzi cause Chagas disease, a chronic condition that can give rise to debilitating cardiac and/or gastrointestinal damage. However, it is unclear why only ~30% of individuals progress to symptomatic pathology, why this can take decades to become apparent, and why there is such a wide range of disease outcomes. Disease pathology is a long-term cumulative process resulting from collateral damage caused by inflammatory immune responses that continually eliminate transient parasite infections in the heart and/or gastrointestinal tract. The guiding principle behind anti-parasitic drug development is that a sterile cure is required to prevent progression to symptomatic pathology. Evidence suggests that the cumulative damage required to reach the symptomatic threshold is determined by a number of factors, including host and parasite genetics, which govern the intensity and location(s) of infection. Therefore, an alternative therapeutic strategy could involve long-term intermittent treatment, which may not confer sterile cure but is able to suppress the parasite burden to a level where the disease does not become symptomatic within the lifetime of the infected individual. To test this hypothesis, we used an experimental murine model that displays both cardiac and digestive tract pathologies. Mice were given intermittent treatment with posaconazole under conditions that initially reduced the parasite burden by >99% but did not confer sterile clearance. Our results show that this did not provide long-term protection against the key cardiac or gastrointestinal manifestations of Chagas disease, and that sterile cure should remain the single goal of the drug development community.