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Background: Human transmission of Chagas disease (CD) most commonly occurs in domiciliary spaces where triatomines remain hidden to feed on blood sources during inhabitants’ sleep. Similar to other neglected tropical diseases (NTDs), sustainable control of CD requires attention to the structural conditions of life of populations at risk, in this case, the conditions of their living environments. Considering socio-cultural and political dynamics involved in dwellings’ construction, this study aimed to explore social factors that contribute or limit sustainability of CD’s prevention models focused on home improvement. Methods and main findings: Using Healthy Homes for Healthy Living (HHHL)—a health promotion strategy focused on improvement of living environments and system-based health promotion—as a reference, a qualitative study was conducted. Research participants were selected from three rural communities of a CD endemic region in southern Ecuador involved in HHHL’s refurbishment and reconstruction interventions between 2013 and 2016. Folowing an ethnographic approach, data were collected through interviews, participant observation, informal conversations and document analysis. Our results indicate that the HHHL model addressed risk factors for CD at the household level, while simultaneously promoting wellbeing at emotional, economic and social levels in local communities. We argue that sustainability of the CD prevention model proposed by HHHL is enhanced by the confluence of three factors: systemic improvement of families’ quality of life, perceived usefulness of control measures, and flexibility to adapt to emerging dynamics of the context. Conclusion: HHHL’s proposed home improvement, facilitated through system-based rather than disease specific health promotion processes, enhances agency in populations at risk and facilitates community partnerships forged around CD prevention. Although an independent analysis of cost-effectiveness is recommended, structural poverty experienced by local families is still the most important factor to consider when evaluating the sustainability and scalability of this model. [ABSTRACT FROM AUTHOR]