BackgroundThe Gran Chaco ecoregion, a hotspot for Chagas and other neglected tropical diseases, is home to >20 indigenous peoples. Our objective was to identify the main ecological and sociodemographic determinants of house infestation and abundance of Triatoma infestans in traditional Qom populations including a Creole minority in Pampa del Indio, northeastern Argentina.MethodsA cross-sectional survey determined house infestation by timed-manual searches with a dislodging aerosol in 386 inhabited houses and administered questionnaires on selected variables before full-coverage insecticide spraying and annual vector surveillance. We fitted generalized linear models to two global models of domestic infestation and bug abundance, and estimated coefficients via multimodel inference with model averaging.Principal FindingsMost Qom households were larger and lived in small-sized, recently-built, precarious houses with fewer peridomestic structures, and fewer livestock and poultry than Creoles’. Qom households had lower educational level and unexpectedly high residential mobility. House infestation (31.9%) was much lower than expected from lack of recent insecticide spraying campaigns and was spatially aggregated. Nearly half of the infested houses examined had infected vectors. Qom households had higher prevalence of domestic infestation (29.2%) than Creoles’ (10.0%), although there is large uncertainty around the adjusted OR. Factors with high relative importance for domestic infestation and/or bug abundance were refuge availability, distance to the nearest infested house, domestic insecticide use, indoor presence of poultry, residential overcrowding, and household educational level.Conclusions and SignificanceOur study highlights the importance of sociodemographic determinants of domestic infestation such as overcrowding, education and proximity to the nearest infested house, and corroborates the role of refuge availability, domestic use of insecticides and household size. These factors may be used for designing improved interventions for sustainable disease control and risk stratification. Housing instability, household mobility and migration patterns are key to understanding the process of house (re)infestation in the Gran Chaco.