Objective: The use of illicit drugs by adolescents is a widespread problem in Taiwan. The aim of this study was to identify risk and protective factors. Design: Web-based survey of high school students. Setting: Senior high schools and vocational high schools in northern Taiwan. Method: Survey data were collected from 15,754 students. Logistic regression analysis examined potential risk and protective factors in individual, family and peer/school domains for lifetime, past-year and past-month illicit drug use and the single and/or multiple use of ketamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and marijuana. Results: The prevalence rates of illicit drug use varied from 1.18% to 2.19% by frequency and type of illicit drug use. Perceived availability of illicit drugs, betel nut chewing, drug use by a family member, peer drug use, missing classes and type of school were significant risk factors in lifetime, past-year and past-month use. Sensation seeking, family member and peer drug use were common factors in ketamine, methamphetamine, MDMA and marijuana use. Drug use by a family member increased the risk of multiple drug use. Smoking was a risk factor for ketamine use. Drug-related knowledge was a protective factor. Conclusions: These findings support the idea that there exist multilevel risk and protective factors for drug use, especially in the family and peer/school domains. School-based interventions should be designed to integrate different levels of risk and protective factors.