Failure to complete high school predicts substantial economic and social disadvantage in adult life. The aim of this study was to determine the longitudinal association of mid-adolescent polydrug use and high school non-completion, relative to other drug use profiles.A longitudinal analysis of the relationship between polydrug use in three cohorts at grade 9 (age 14-15 years) and school non-completion (reported post-high school).A State-representative sample of students across Victoria, Australia.A total of 2287 secondary school students from 152 high schools. The retention rate was 85%.The primary outcome was non-completion of grade 12 (assessed at age 19-23 years). At grade 9, predictors included 30-day use of eight drugs, school commitment, academic failure and peer drug use. Other controls included socio-economic status, family relationship quality, depressive symptoms, gender, age and cohort.Three distinct classes of drug use were identified-no drug use (31.7%), mainly alcohol use (61.8%) and polydrug use (6.5%). Polydrug users were characterized by high rates of alcohol, tobacco and cannabis use. In the full model, mainly alcohol users and polydrug users were less likely to complete school than non-drug users [odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.17-2.03) and OR = 2.51, 95% CI = 1.45-4.33), respectively, P < 0.001]. These effects were independent of school commitment, academic failure, peer drug use and other controls.Mid-adolescent polydrug use in Australia predicts subsequent school non-completion after accounting for a range of potential confounding factors. Adolescents who mainly consume alcohol are also at elevated risk of school non-completion.