Although rare, there have been isolated reports of autochthonous transmission of Trypanosoma cruzi Chagas in the United States. In June 2006, a human case of domestically transmitted T. cruzi was identified in southern Louisiana. To examine the localized risk of human T. cruzi infection in the area surrounding the initial human case, environmental surveys of households in the area and a serological survey of the residents were performed between September 2008 and November 2009. Human T. cruzi infection was determined using a rapid antigen field test, followed by confirmatory enzyme-linked immunosorbent assay testing in the laboratory. A perimeter search of each participating residence for Triatoma sanguisuga (LeConte), the predominant local triatomine species, was also performed. No participating individuals were positive for antibodies against T. cruzi; however, high levels of T. cruzi infection (62.4%) were detected in collected T. sanguisuga. Households with T. sanguisuga presence were less likely to use air conditioning, and more likely to have either chickens or cats on the property. While the human risk for T. cruzi infection in southeastern Louisiana is low, a high prevalence of infected T. sanguisuga does indicate a substantial latent risk for T. cruzi peridomestic transmission. Further examination of the behavior and ecology of T. sanguisuga in the region will assist in refining local T. cruzi risk associations.