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Serological screening for celiac disease (CD) can detect a large number of otherwise undiagnosed patients based on the sequential evaluation of serological tests and intestinal biopsy. The aim of this study was to compare the screening value for CD of two different protocols for the same community-based population.We screened 1000 consecutive subjects (497 women, age range 16–71 yr) attending a centralized laboratory for obligatory prenuptial blood tests. Serum samples obtained from all subjects were processed using two different protocols: 1) a three-level classic screening consisting of the parallel use of IgG and IgA antigliadin antibodies as first level, followed by endomysial antibodies and total serum IgA for positive patients, and finally, intestinal biopsy of positive patients; and 2) a study screening protocol consisting of the parallel use of a commercial guinea pig antitissue transglutaminase antibody and total serum IgA as first line, endomysial antibodies (type IgA and/or IgG) for positive patients, and finally, intestinal biopsy.The classic screening protocol identified five subjects who were eligible for intestinal biopsy, which confirmed the presence of CD in all (prevalence 5.0 × 1000, 95% CI = 1.6–11.6). Using the study algorithm, we detected seven new patients including the five patients detected by the first protocol (prevalence 7.0 × 1000, 95% CI = 2.8–14.4). The two additional patients diagnosed using the proposed algorithm had positive IgG antigliadin antibodies and normal total serum IgA and were not detected by the classic protocol. Both patients were endomysial antibodies positive. The comparative analysis showed that the classic approach was more expensive (U.S. $4687 per new patient detected) compared with the proposed study algorithm (U.S. $3006).Our data showed that a new screening protocol using antitissue transglutaminase as first line followed by endomysial antibodies is a cost-effective screening and yielded more realistic figures of prevalence for CD in a community setting than the classic three-level sequential evaluation using antigliadin antibodies.