Opioid misuse has caused serious public health and social problems. However，opioid misuse among Chinese adolescents is still understudied. Macao，due to its gaming industry and adjacency to the Golden Triangle，is threatened by a more serious drug misuse crisis. In response to such a crisis，Macao Government has carried out a series of prevention and evaluation programs. Based on the “Adolescents and Drugs in Macao” surveys，the current study explores the patterns，trends and risk factors of opioid misuse among middle and high school students in Macao. The results showed that compared with the West，the opioid misuse prevalence among Macao adolescents remained low. Adolescents’ risk perception of drug use was on a downward trend，while approval of drug use and perceived availability of drugs was on an upward trend. Adolescents’ drug use behavior，perception and attitude toward drug use showed significant gender and grade differences. Adolescents’ perception and attitude toward drug use，drug user peers，and current smoking behavior were significant risk factors for their opioid misuse behavior. The results suggested that drug misuse prevention education for adolescents should adapt to the changes in adolescents’ cognition and behavior related to drug use and help adolescents to develop skills in rejecting hazardous peer cultures. Diverse substance abuse prevention resources need to be integrated to fit with the diversification of substance abuse.