Despite limited and ambiguous empirical data, substance use-related problems have been assumed to be rare among patients with autism spectrum disorders (ASD). Using Swedish population-based registers we identified 26,986 individuals diagnosed with ASD during 1973-2009, and their 96,557 non-ASD relatives. ASD, without diagnosed comorbidity of attention deficit hyperactivity disorder (ADHD) or intellectual disability, was related to a doubled risk of substance use-related problems. The risk of substance use-related problems was the highest among individuals with ASD and ADHD. Further, risks of substance use-related problems were increased among full siblings of ASD probands, half-siblings and parents. We conclude that ASD is a risk factor for substance use-related problems. The elevated risks among relatives of probands with ASD suggest shared familial (genetic and/or shared environmental) liability.