It is now evident that both developed and developing countries are experiencing many aspects of inappropriate use of drugs in their health care facilities. This is the first study in the region performed to examine the most common problems of irrational use of drugs and their causes in two Middle East countries – Jordan and Syria. Ninety senior participants from Jordan (50–15 physicians and 35 pharmacists) and Syria (40–12 physicians and 28 pharmacists) were enrolled in this study. The participants were asked to fill two questionnaires that deal with the problems and causes of irrational use of drugs in their country. Additionally, the participants were asked to perform a prescription analysis using WHO prescribing indicators on 40 prescriptions taken randomly from a comprehensive health centre in their country. The main drug use problems identified in the two countries were almost the same, but they vary in the percentage of occurrence and include excessive use of antibiotics and antidiarrhoeals, overprescribing of nonsteroidal anti-inflammatory drugs, prescribing by tradename, excessive use of antibiotics to treat minor upper respiratory infections and self-medication by the public. The main causes of irrational use of drugs were poor medical records, lack of patient education about illnesses and drugs, no family doctor system, lack of standard treatment guidelines and lack of continuing medical education for doctors and pharmacists. The results of this study are important for decision-makers to utilise when putting policies and strategies to improve the use of drugs in both countries.