Immunoglobulin A (IgA) deficiency occurs more frequently in patients with celiac disease (CD) than in the general population and can lead to false-negative results in the best serologic test for CD, endomysial IgA (EMA). To evaluate the impact of IgA deficiency on serologic detection of CD in a reference laboratory setting, IgA levels were measured in 510 consecutive serum specimens submitted for testing for EMA; 510 consecutive serum specimens submitted for Helicobacter pylori IgG testing served as a gastrointestinal symptom control group. The frequency of IgA deficiency was significantly higher among the specimens submitted for testing for EMA (5.1%) than among the specimens from the symptom control group (1.4%). Three subsets of sera from the group of specimens submitted for testing for EMA were then tested by additional serologic assays for CD; these subsets were EMA-positive sera (n = 25), EMA-negative, IgA-deficient sera (n = 26), and control sera (from EMA-negative, IgA-nondeficient patients age matched to IgA-deficient patients; n = 26). The proportions of EMA-positive sera positive by other assays for CD were 92% for transglutaminase IgA (TG-IgA), 80% for gliadin IgA, 84% for gliadin IgG, 60% for endomysial IgG (EMG), and 32% for transglutaminase IgG (TG-IgG). Very low proportions (0 to 8%) of IgA-deficient sera and control sera were positive for TG-IgA, gliadin IgA, EMG, and TG-IgG. Eight of 26 (31%) IgA-deficient serum samples were positive for gliadin IgG, whereas 3 of 26 (12%) control serum samples were positive for gliadin IgG, but this difference was not statistically significant. Physicians supplied clinical data for 18 of 26 patients with IgA deficiency; only 4 patients had undergone small-bowel biopsy, and 0 of 4 patients showed villous atrophy. These findings show that IgA deficiency is found more frequently among sera submitted for testing for EMA in a reference laboratory setting, but there was no clear-cut serologic or clinical evidence of CD in EMA-negative, IgA-deficient patients.