Estimates of the diagnostic performance of serologic testing and HLA-DQ typing for detecting celiac disease have mainly come from case-control studies. To define the performance of serologic testing and HLA-DQ typing prospectively. Prospective cohort study. University hospital. Patients referred for small-bowel biopsy for the diagnosis of celiac disease. Celiac serologic testing (antigliadin antibodies AGA, antitransglutaminase antibodies TGA, and antiendomysium antibodies EMA) and HLA-DQ typing. Diagnostic performance of serologic testing and HLA-DQ typing compared with a reference standard of abnormal histologic findings and clinical resolution after a gluten-free diet. Sixteen of 463 participants had celiac disease (prevalence, 3.46% 95% CI, 1.99% to 5.55%). A positive result on both TGA and EMA testing had a sensitivity of 81% (CI, 54% to 95.9%), specificity of 99.3% (CI, 98.0% to 99.9%), and negative predictive value of 99.3% (CI, 98.0% to 99.9%). Testing positive for either HLA-DQ type maximized sensitivity (100% CI, 79% to 100%) and negative predictive value (100% CI, 98.6% to 100%), whereas testing negative for both minimized the negative likelihood ratio (0.00 CI, 0.00 to 0.40) and posttest probability (0% CI, 0% to 1.4%). The addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, did not change test performance compared with either testing strategy alone. Few cases of celiac disease precluded meaningful comparisons of testing strategies. In a patient population referred for symptoms and signs of celiac disease with a prevalence of celiac disease of 3.46%, TGA and EMA testing were the most sensitive serum antibody tests and a negative HLA-DQ type excluded the diagnosis. However, the addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, provided the same measures of test performance as either testing strategy alone.