We examined temperament and character profiles of 128 adults with autism spectrum disorder (ASD) or attention deficit and hyperactivity disorder (ADHD). Participants completed the abbreviated Temperament and Character Inventory. The ASD and ADHD groups showed distinct temperament profiles (ADHD: high novelty seeking, ASD: low reward dependence, high harm avoidance) and low character scores in both groups. We then stratified ASD and ADHD into current substance use disorder (SUD+), former (SUDˆ), or no history of Substance Use Disorder (SUD−). Novelty seeking and reward dependence were only significantly lower for ASD/SUD−, but normal for ASD/SUDˆ and ASD/SUD+ subgroups. Persistence scores were highest in both SUDˆ subgroups. We concluded that temperament profiles of ASD and ADHD patients differ significantly, and are similar to profiles reported in earlier studies, but appear to depend on the SUD status. Surprisingly, normal social orientation is found in ASD patients with former or current SUD. High persistence scores characterize patients who overcome SUD.