Adverse events (AE) are an ongoing challenge in healthcare. Apart from having a significant impact on patient morbidity and mortality, AE also result in increased healthcare costs due to longer hospital stays. However, little is known about AE occurrence and their risk factors in Tunisian healthcare system. To determine the incidence of severe adverse events (SAEs) and identify risk factors associated with SAE during hospitalization in a Tunisian University Hospital. A case-control study with incident cases was conducted including all patients hospitalized in the Teaching Hospital Farhat Hached within a one-month period in 13 clinical units. Medical records for caseswere selected by using stratified random sampling. The sample size was proportional to the number of admissions in each of 13 clinical departments. Controls were matched by the service and the duration of hospitalization preceding the appearance of SAE. Risk factors were collected and analyzed by conditional stepwise logistic regression. Overall, 304 controls were matched to cases, totalizing 456 patients. Multivariate conditional stepwise logistic regression analysis showed that night-time admission, hospitalization in the last six months, difficulty of communication, longer surgical operation, biopsy, presence of at least two medical devices, exposure to peripheral venous catheter, exposure to more than four medications and blood transfusion were considered as independent risk factors of SAE occurrence. Our results highlighted care-related risk factors such as catheters, blood transfusion and polymedication, which underlined the need to strengthen the care safety by focusing efforts especially in the field of hospital hygiene and infection control as well as pharmacovigilance