Objective: To investigate psychoactive substance abuse and associated factors among middle school students in Liaoning, and to provide policy suggestions and reference opinions for relevant departments. Methods: A questionnaire survey was conducted among 12 598 middle school students in 10 cities of Liaoning by multi stage stratified cluster sampling. Multivariate Logistic regression model was used to analyze associated factors of psychoactive substance abuse. Results: About 0.94% ( n =118) of all participants reported substance abuse behavior, the highest abuse rate was in the third grade students in vocational middle school, the most common psychoactive substance was “laughing balloon”, accounting for 0.57%. Multivariate Logistic regression analysis revealed that girls, moderate academic burden were generally negatively associated with more psychoactive substance use( OR = 0.57 , 0.58, P <0.05). Academic performance class was ranked in the last ten, monthly pocket money more than 500 yuan and sleep with medication were generally positively associated with more psychoactive substance use ( OR =1.93, 2.52, 4.29, P < 0.05 ). Conclusion The problem of psychoactive substance abuse among middle school students can not be ignored. Effective prevention and control of psychoactive substance abuse can be achieved through publicity, education, awareness raising, early intervention, counseling and treatment, and through coordination of adolescents, families, schools, government and the society.