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Objective: This study was carried out to determine the prevalence of substance use, changing substance preference in between 1996-2015 follow up period, and risk factors related to illegal substance use among high school students in TRNC. Methods: The study was conducted among 2079 grade 10 high school students in TRNC in May and June 2015. The questionnaire of the study was based on questions from the European Schools Research Project on Alcohol and Other Drugs (ESPAD). The similar form was used in previous 1996, 1999, 2004 and 2011 high school studies and data was given in comparison with those studies in TRNC. Result: In this study decreased was seen at least once lifetime smoking rate from 45.7% in 1996 to 33% in 2015 and alcohol use from 80.8% in 1996 to 70.7% in 2015, but illegal substance use was increased from 2% in 1996 to 5.2% in 2015. The use of volatile substances and sedative-hypnotic tablets tend to decline due to years, but they are the most common substances after cigarette and alcohol. Cannabis and synthetic cannabinoid are the most commonly used illicit substances. It has been found that the trial rate of ecstasy has increased rapidly in recent years. The risk factors for illicit drug use are being male, being 17 and older, failing grade, smoking and alcohol use, having been drunk. Conclusion: The result of the study indicates that the rate of psychoactive substance use among high school students in TRNC is lower than in European countries and USA. But there is an increase in use of illicit substances. Especially in the high school youth of TRNC, besides smoking and alcohol use, volatile substances, cannabis, synthetic cannabinoid and ecstasy should be taken should be taken into consideration for prevention program. [Anadolu Psikiyatri Derg 2017; 18(5.000): 428-437]