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Antipyretic drugs such as suspensions of Mefenamic acid (Ponstan), Ibuprofen and paracetamol (acetaminophen) are the most common drugs that wildly used in children to decrease the fever, pain and inflammation, and from clinical observations of children using these drugs, found they cause gastrointestinal complications and from this, the idea of this research was to find the effect of these drugs on the mucous membrane of the gastrointestinal tract in Swiss albino mice.In the present study, we used 30 mice classified into five groups which are G1 as control group, G2 receive 15 mg kg -1day-1 panadol, G3 receive 30 mg kg-1day-1ibuprofen, G4 receive 5 mg kg-1 day-1 Ponestan and G5 receive a combination of panadol and ibuprofen in same the previously doses respectively for 7 days. The gastric histological sections of G2 were normal mucosal, G4 shown mild mucosal glandular hyperplasia, while G3 and G5 groups appear flat mucosal surface with submucosal hyperplasia of gland mild atypical cells, and G2 showing mucosal glandular hyperplasia. The intestine histological sections of G2 appears normal intestinal villi with mild inflammatory cells infiltration, G3 shown dispersed slight shortening of intestinal villi with mild inflammatory cells infiltration, finally G4 and G5 shown villi hyperplasia with a slight widening of villi with mild inflammatory cells infiltration. NSAIDs are available over-the-counter drugs for adult and in pediatric population And it is considered a safe medicine if used in properly dose in the short-term, the decision to pick an antipyretic should be dictated by safety, efficacy, effectiveness, duration of action and the integrity of the patient gut.