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Background: It has been suggested that high titres of tTG are associated with elevated positive predictive values (PPV) for celiac disease. However, the PPV of a strongly positive tTG will depend on the celiac disease prevalence in the different risk groups of the diseaseAims: To assess the PPV of a strongly positive tTG for celiac disease. In addition, to calculate the post-test probability for celiac disease of a strongly positive tTG in a setting of routine clinical practice.Methods: 145 consecutive celiac disease patients with positive tTG, and with a small bowel biopsy were included. The PPV for different cut-off points of tTG levels for the diagnosis of celiac disease was assessed. In addition, the cut-offs associated with higher PPV were used to calculate the positive likelihood ratio. A simulation in a setting of routine clinical practice was performed to calculate the post-test probability of celiac disease.Results: No cut-off level was associated with a PPV of 100%. A cut-off of 80 U/mL (11.4 × upper normal limit) was associated with the higher PPV value of 98.6%. In the most frequent clinical situations, which in general have a pre-test probability < 10%, the post-test probability after having a strongly positive tTG was 90% or less.Conclusions: A strongly positive tTG should not be enough to diagnose celiac disease in the most frequent clinical situations, small bowel biopsy remaining as the gold standard in these cases.