Due to the widespread use of anti-inflammatory drugs in clinical practice in various clinical settings and the ease of issue without prescription, many patients are exposed to risks associated to these drugs and particularly to drug interactions. The purpose of this review is to deal with the safety parameters of main anti-inflammatory agents, especially NSAIDs including coxibs, and the different drug interactions with a special emphasis on clinical relevance and recommendations in current practice. We will present consecutively different interactions between anti-inflammatory agents and frequently used drugs. In particular, association between anti-inflammatory drugs and anticoagulants could induce severe complications. Hemorrhagic complications and particularly gastrointestinal bleeding will be discussed together with potential treatment adjustment and likely benefits of new therapies such as specific antagonist of active factor X or II. On the other hand, anti-hypertensive therapies, non specific cytochrome dysregulations and particularly the question of antiarrhythmic drugs, the problem of proton pump inhibitors and specific clinical settings such as drug interactions in elderly are discussed.