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In Italy, HDV infection endemicity has greatly decreased overtime. Migratory flow may change this scenario as migrants often come from high HDV endemicity areas. Here, we studied characteristics of HDV infection in Italy, particularly addressed to the birth area of subjects. Chronic HBsAg carriers consecutively referring to 9 units in Italy prospectively enrolled for a six‐month period in 2019 were tested for anti‐HDV by ELISA. Multiple logistic regression analysis was performed to identify anti‐HDV positivity independent predictors. A total of 894 HBsAg‐positive subjects were enrolled. Of them, 786 (87.9%) were tested for anti‐HDV. Anti‐HDV overall prevalence was 9.9% (6.4% in Italian natives and 26.4% in non‐natives; P <.001). HDV‐RNA was checked in 63 (80.8%) of the 78 anti–HDV+ subjects, and 49 (77.8%) tested positive. Compared to non‐natives, Italians were more likely males (male/female 1.6 vs 0.6; P <.05) and older (median age 57 years vs 46 years; P <.05). Multivariate analysis showed that non‐natives (OR = 6.02; CI 95% = 3.06‐11.84) and cirrhosis (OR 9.6; CI 95% = 5.39‐17.30) were independently associated with anti‐HDV positivity. A remarkable changing pattern in some characteristics of anti–HDV‐positive subjects was observed over 1987‐2019: a decreasing male/female ratio, an increasing mean age and proportion of cirrhotic subjects. Anti‐HDV prevalence decreased from 7.4% to 6.4% among Italians, increasing from 12.2% to 26.4% among non‐natives during 2001‐2019. Hence, HDV infection in Italians is further decreasing and mostly affects old people and subjects with advanced disease reflecting a survival effect. Conversely, non‐natives are sixfold more likely anti–HDV‐positive with an increasing trend. Migratory flow may be a new challenge for HDV infection at the beginning of the third millennium. [ABSTRACT FROM AUTHOR]