Introduction: Although substance use has increased in recent years in Turkey, it is still lower than in other European countries. Turkey is home to the largest Syrian refugee population. In this study, it was aimed to evaluate the prevalence of tobacco, alcohol, and substance use among local people living in city centers and refugees living in refugee camps in Şanlıurfa. Methods: The study was based on a cross-sectional epidemiologic survey conducted with a total of 6041 people, 4040 (67%) from camps and 2001 (33%) from districts. Face-to-face interviews were accompanied by local interviewers or interpreters who spoke Arabic, and a survey form used in our country for drug addiction screening was used. According to the number of samples selected, households with proportional distribution were chosen from the districts, which were selected from the address based from Turkish Statistical Institute. In the refugee camps, interviews were conducted in tents selected using a random numbers table according to the number of samples. Results: The lifetime prevalence of tobacco use was 22.3% (n=902) in the camps, whereas in the districts this rate was 33.5% (n=670). The lifetime prevalence of alcohol use was found as 0.2% in the camps and 3.5% in the districts. The lifetime prevalence of substance use was found as 2.6% in the camps and 4.3% in the districts. The most commonly used substance type was cannabis. Some 45.7% of the people who used a substance in the camps were male and 54.3% were female. In districts, these rates were 64.4% and 35.6%, respectively. Conclusion: Alcohol and substance use rates are low in Turkey compared with most countries in the world. Substance use in the city center is higher than in refugee camps in Şanlıurfa. Substance use is a significant mental health problem that concerns every community including refugees. Identifying characteristics and attitudes related to substance use may help to improve policies regarding protective measures.