Objective: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and the community. Despite this, there is limited information in the literature regarding drug interaction categories responsible for causing ADRs.In this study we investigated the drug combinations most frequently co-reported as interacting in the WHO Global Individual Case Report (ICSR) Database, VigiBase, and categorised them in respect to the drug interaction mechanism. Methods: Reports with drug combinations coreported as interacting on at least 20 reports in VigiBase during the past 20 years were included in the study. Each drug combination was reviewed in the literature to identify the mechanism of interaction and classified as pharmacodynamic and/or pharmacokinetic. Report characteristics were also analysed. Results: In total 3766 case reports of drug interactions from 47 countries were identified. Of 123 different drug combinations 113 were described in the literature to interact. The mechanism were categorised as: pharmacodynamic in 46(41%), pharmacokinetic in 28(25%), a combination of both types in 18(16%), and unidentified in 21(19%) drug interactions. Pharmacodynamic drug interactions primarily concerned pharmacological additive effects whereas enzyme inhibition was the most frequent pharmacokinetic interaction. The reviewed combinations primarily implicated drugs such as warfarin, heparin, carbamazepine and digoxin. Conclusions: Drug interactions reported on globally collected ADR reports covers both pharmacodynamic, specifically additive pharmacological effects, and pharmacokinetic mechanisms primarily accredited inhibition of hepatic CYP enzymes. These ADR reports often concerns serious threats to patients' safety, particularly related to usage of high risk drugs such as warfarin and heparin.