Polydrug use is relatively common among adolescents. Psychological distress is associated with the use of specific drugs, and may be uniquely associated with polydrug use. The purpose of this study was to test the association of psychological distress with polydrug use using a large adolescent sample. The sample consisted of 10,273 students aged 12-17 years from the State of Victoria, Australia. Participants completed frequency measures of tobacco, alcohol, cannabis, inhalant, and other drug use in the past 30 days, and psychological distress. Control variables included age, gender, family socioeconomic status, school suspensions, academic failure, cultural background, and peer drug use. Drug-use classes were derived using latent-class analysis, then the association of psychological distress and controls with drug-use classes was modeled using multinomial ordinal regression. There were 3 distinct classes of drug use: no drug use (47.7%), mainly alcohol use (44.1%), and polydrug use (8.2%). Independent of all controls, psychological distress was higher in polydrug users and alcohol users, relative to nondrug users, and polydrug users reported more psychological distress than alcohol users. Psychological distress was most characteristic of polydrug users, and targeted prevention outcomes may be enhanced by a collateral focus on polydrug use and depression and/or anxiety.