Aim: This study aims to investigate self-efficacy and the related factors of students enrolled in two different types of high schools regarding protection from substance abuse.Materials and Methods: This study was conducted with 170 volunteer students enrolled in an Anatolian High School in city center and a Technical High School in district in the academic year 2018-2019. Data were collected using a sociodemographic characteristic form and Self-Efficacy Scale for Protection from Substance Abuse. Data were analyzed using SPSS 16.0 software, percentage, chi-square, t-test and Anova test for independent groups. Results: The mean age of the participants was 15.2±0.85. Of them, 58.8% were female and 55.3% were enrolled in Anatolian High School, 11.8% both smoked and used alcohol. There was a significant relationship between the mean score on the Self-Efficacy Scale for Protection from Substance Abuse and gender, residence, mother’s education background, income level, type of high school, alcohol and smoking habits (p<.05). Substance abuse protection self-efficacy levels of the Technical High School students were lower than that of the Anatolian High School students. Conclusion: At risk students of substance abuse were male, those with lower income, those living in districts and villages, the Technical High School students, smokers and alcohol users. The high-risk groups should be diagnosed early and be aware of the risk. Early intervention measures should be taken for high-risk groups. These high-risk groups in schools should be closely monitored and, if necessary, collaborated with the family.