Soil-transmitted helminth (STH) infections rank among the most prevalent communicable diseases of humans, yet detection of these parasites is mostly restricted to identifying active infection through fecal examinations. Currently, there are no commercial diagnostic tools to identify a prior whipworm or hookworm exposure, and the few serological assays for roundworm infection have not been well validated for crossreactivity or infections in humans. Such diagnostic restrictions limit the range of scientific and clinical questions that surround STH exposures and their implicated relationship to chronic diseases, such as autoimmunity, allergy, and cancer. The goal of this investigation was to evaluate the diagnostic potential of 13 STH recombinant proteins. As there are no gold standard tests to verify positive STH antisera, we used sera from active STH-infected individuals in Honduras (measured by quantitative real-time polymerase chain reaction of helminth DNA in stool) and compared antibody recognition by both ELISA and western blot with nonendemic control sera from age-matched individuals in the United States split into screening and validation cohorts. One recombinant protein, rTm-WAP49, shows potential as a whipworm diagnostic tool by receiver-operator characteristic analysis (area under the curve = 0.997, P <0.001) and indirect ELISA with sensitivity of 100% and specificity of 91% as defined by mean plus two SDs from the nonendemic screening cohort. We found discrepancies in serological recognition of previously tested STH antigens, highlighting the need to consider different technologies before down selection of a promising diagnostic candidate and screen multiple endemic populations before widely accepting an STH serological assay.