The objectives of this study were to analyze in-hospital adverse drug events (ADEs) in Portuguese public hospitals, and their association with mortality and the duration of hospitalization. We analyzed an administrative database containing the registration of all hospitalizations occurring in Portuguese public hospitals in 2013-2015. ADEs were identified using the codes E850-858.9 and E930-949.9 from ICD-9-CM. We identified all episodes with registration of in-hospital ADE and we compared them with a random sample of an equal number of episodes with no events recorded. A total of 3,041,443 cases were analyzed, 60,521 presented at least one ADE from which 17,213 occurred in hospital context. The most frequent drug classes associated with ADE were the antineoplastics/immunosuppressant drugs, antibiotics and steroids. Patient characteristics associated with a greater occurrence of in-hospital ADEs (all with p < 0.001) were medical admissions (OR = 1.29), the diagnosis - myeloid leukaemia (OR = 18.63), nephrotic syndrome (OR = 15.75), pneumonia (OR = 1.33) -, a higher number of secondary diagnoses (OR = 1.27), and increased duration of hospital stay (OR = 1.06). Hospitalizations with records of in-hospital ADEs presented a significantly higher mortality (9.6% vs. 4.5) and duration of hospitalization (22.6 vs. 6.4 days). ADEs were shown to be directly associated with an increase in the duration of hospital stay of 8.18 days. This study adds some interesting insights related to the most frequent drug classes and patient characteristics that can influence the frequency of ADEs in Portuguese public hospitals and also the burden of injury resulting from them.