This study prospectively examined neuropsychological (NP) functioning associated with adolescent substance use and withdrawal. Participants were youths with histories of substance use disorders (n = 47) and demographically comparable youths with no such lifetime histories (n = 26). They were followed with NP testing and substance involvement interviews at 7 time points spanning 8 years, from ages 16 to 24, on average. After controlling for recent use, age, education, practice effects, and baseline NP functioning, substance use over the 8-year follow-up period significantly predicted performances on tests of memory and attention at Year 8. Additionally, withdrawal symptoms during the follow-up predicted visuospatial and attention scores at Year 8. Findings suggest that use and withdrawal may differentially impact neurocognitive functioning during youth, with heavy use leading to learning, retention, and attentional difficulties, and withdrawal leading to problems with visuospatial functioning.