Substance use in young adulthood and polysubstance use (PSU), in particular, pose unique risks for adverse consequences, including overdose. Prior research on young adult PSU has identified multiple classes of users, but most work has focused exclusively on college students. We examined PSU patterns by age and college attendance during young adulthood in two nationally-representative samples. Using National Epidemiological Survey on Alcohol and Related Conditions (NESARC) Wave 1 and NESARC-III datasets, multi-group latent class analysis (MG-LCA) was employed to examine PSU patterns based on age (18-24 vs. 25-34) and determine whether solutions were invariant by college attendance/graduation. Classes were estimated by binary past-year use of sedatives, tranquilizers, opioids/painkillers, heroin, amphetamines/stimulants, cocaine, hallucinogens, club drugs, and inhalants, and past-year frequency of alcohol, cigarette, and cannabis use. PSU patterns largely replicated across waves. Model fit supported 3-class solutions in each MG-LCA: low frequency limited-range PSU, medium-to-high frequency limited-range PSU, and extended-range PSU. Apart from one model, MG-LCA solutions were not invariant by college attendance/graduation, suggesting important differences between these groups. Except for alcohol, cannabis, and cigarette use frequency, results supported the maturity principle of substance use, with probabilities of illicit and prescription drug use declining in the older age group. Findings also supported examining college and non-college youth separately when studying PSU. Extended-range polysubstance users may be uniquely vulnerable to co-ingesting substances, particularly for non-graduates, warranting future research to classify patterns of simultaneous PSU and identify predictors and consequences of high-risk combinations (e.g., alcohol and opioids).