Chagas disease affects an estimated 300,000 individuals in the US. Diagnosis in the chronic phase requires positive results by two different IgG serological tests. Three ELISAs (Hemagen, Ortho, Wiener) and one rapid test (InBios) are FDA-cleared, but comparative data in US populations are sparse. Methods: We evaluated 500 seropositive and 300 seronegative blood donor plasma samples. Country of birth was known for 255 seropositive specimens and grouped into regions: Mexico (n=94), Central

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... (n=88) and South America (n=73). Specimens were tested by the four FDA-cleared IgG serological assays. Test performance was evaluated by two comparators and a latent class analysis. Results: InBios had the highest sensitivity (97.4-99.3%), but lowest specificity (87.5-92.3%). Hemagen had the lowest sensitivity (88.0-92.0%), but high specificity (99.0-100.0%). Sensitivity was intermediate for Ortho (92.4-96.5%) and Wiener (94.0-97.1%); both had high specificity (98.8-100.0% and 96.7-99.3%, respectively). Antibody reactivity and clinical sensitivity was lowest in donors from Mexico, intermediate in those from Central America and highest in those from South America. Conclusions: Our findings provide an initial evidence base to improve laboratory diagnosis of Chagas disease in the US. The best current testing algorithm would employ a high sensitivity screening test followed by a high specificity confirmatory test.