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Although anti-tissue transglutaminase antibodies (anti-tTG) are effective for celiac disease (CD) routine laboratory screening, there are no studies evaluating correlation between degree of intestinal damage and positivity to anti-tTG. Since recent studies showed that anti-gliadin (AGA) and anti-endomysium (EMA) antibodies are ineffective in diagnosing mild gluten-sensitive enteropathy, the aim of this study was to evaluate the prevalence of anti-tTG in different degrees of intestinal damage of celiac patients and whether there is a correlation between serum value of anti-tTG and the degree of histologic damage.We studied 119 consecutive adult patients affected by CD (47 men and 72 women; mean age, 28 years; range, 22–51 years). All patients were stratified for histologic damage according to Marsh classification, and in all of them an anti-tTG evaluation was performed.Marsh I lesions were present in 13 patients (10.92%), Marsh II in 24 anti-tTG (20.16%), Marsh IIIa in 27 anti-tTG (22.68%), Marsh IIIb in 31 anti-tTG (26.05%) and Marsh IIIc in 24 anti-tTG (20.16%). Anti-tTG positivity was ranging from 1 of 13 anti-tTG (7.69%) in Marsh I lesions to 23 of 24 anti-tTG (95.83%) in Marsh IIIc lesions respectively (P < 0.005), while mean serum value of anti-tTG ranged from 3.61 (range, 0.7–9.2) UA/mL in Marsh I lesions to 7.3 (range, 1–25.1), 18.5 (range, 1.8–56.2), 36 (range, 3.7–83.5) and 74.95 (range, 6.5–257) UA/mL in Marsh II, IIIb and IIIc lesions respectively (P < 0.005).Our study showed that anti-tTG prevalence and their mean serum value was higher in celiacs with severe enteropathy (Marsh IIIb-c lesions) than in those showing slight enteropathy (Marsh I-IIIa). So, serologic tests without histologic evaluation may underestimate the real prevalence of CD and there is the risk of delaying the diagnosis of CD in patients who run an increased risk of deficiencies, non-malignant conditions and malignancy.