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Introduction: Chagas disease, a neglected tropical disease that affects millions of Latin Americans, has been effectively controlled in Guatemala after multiple rounds of indoor residual insecticide spraying (IRS). However, a few foci remain with persistent Triatoma dimidiata infestation. One such area is the municipality of Comapa, Department of Jutiapa, in the southeastern region of Guatemala, where control interventions appear less effective. We carried out three cross sectional entomological and serological surveys in Comapa to evaluate a decade of vector control activities. Baseline serological (1999) and entomological (2001-2) surveys were followed by three rounds of insecticide applications (2003-2005) and intermittent focal spraying of infested houses, until approximately 2012. Household inspections to determine entomological indices and construction materials were conducted in 2001, 2007 and 2011. Seroprevalence surveys were conducted in school-age children in 1999, 2007 and 2015, and in women of child bearing age (15-44 years) only in 2015. After multiple rounds of indoor residual sprayings (IRS), the infestation index decreased significantly from 39% (2001-2) to 27% (2011). Household construction materials alone predicted <10% of infested houses. Chagas seroprevalence in Comapa declined in school-aged children by 10-fold, from 10% (1999) to 1% (2015). However, seroprevalence in women of child bearing age remains >10%., Conclusion: After a decade of vector control activities in Comapa, there is evidence of significantly reduced transmission. However, the continued risk for vector-borne and congenital transmission pose a threat to the 2022 Chagas disease elimination goal. Systematic integrated vector control and improved Chagas disease screening and treatment programs for congenital and vector-borne disease are needed to reach the elimination goal in regions with persistent vector infestation., Competing Interests: The authors have declared that no competing interests exist.