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We conducted a disproportionality analysis of the adverse events (AEs) of EGFR-TKIs (gefitinib, erlotinib, afatinib, osimertinib) by data mining using the FDA adverse event reporting system (AERS) database, and by calculating the reporting odds ratios (ROR) with 95% confidence intervals. The FDA AERS database contained 27,123 EGFR-TKI-associated AERs within the reporting period from January 1, 2004 to March 31, 2018. Thirty-three preferred terms (PTs) were selected for analysis, and significant RORs were most commonly observed in the skin, nail, gastrointestinal tract, hepatic, eyes, and lungs. Unexpected adverse drug reactions were found in the \u201cintestinal obstruction\u201d and \u201chypokalaemia\u201d in gefitinib and erlotinib, \u201chyponatraemia\u201d in gefitinib, erlotinib and afatinib, \u201calopecia\u201din erlotinib, \u201chair growth abnormal\u201d in afatinib, but not in \u201cnausea\u201d and \u201cvomiting\u201d listed on drug labels. 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