BACKGROUND Self-medication, often without adult guidance, has been reported to be a common practice during adolescence. Similar to other preventable health-risk behaviors initiated in early adolescence, it has become a cause for concern universally. OBJECTIVE This study examines the prevalence of self-medication with both prescribed and non-prescribed (OTC) medications, related health complaints, sources of drugs, and sources of drug recommendation, and gender differences related to self-medication among expatriate high school students in the United Arab Emirates (UAE). METHODS A cross-sectional survey was conducted among 324 expatriate students through a validated, self-administered questionnaire and data was analyzed using SPSS 19 version. Means and proportions were calculated and Pearson Chi-square test of significance was used to analyze association among variables. RESULTS Majority of the participating students, almost equally distributed by gender, was aged 16 to 17 years. The period prevalence rate of self-medication with prescribed and OTC medications were 89.2%, which did not vary with age, gender, ethnicity or parents' educational level. The most common sources of drug and drug recommendation were community pharmacies and parents respectively. Headache and fever were the common self-medicated conditions and consequently, analgesics and antipyretics were most commonly used both in the previous two weeks and the previous year prior to the survey. A high prevalence of self-medication with antibiotics (53%) and sedative/hypnotics (27%) was also observed. A female excess emerged for certain health complaints and use of medicines except for the use of anti-allergic and herbal/homeopathic drugs. CONCLUSIONS This is the first study to explore self-medication practices among high school students in UAE and provides baseline data critical in creating awareness about the risks and benefits of self-medication. Health care providers, educators and parents should be actively involved in health education strategies for inculcating responsible self-medication practices in the adolescent population of UAE.