To examine whether young adult opioid misuse reflects a general tendency toward substance use and is influenced by general substance use risk or whether it is a different phenomenon from other drug use. At ages 23 (2016) and 26 (2019), a panel of young adults (n = 3794 to 3833) in the United States self-reported their past-month substance use (opioid misuse, heavy drinking, cigarettes, cannabis) and substance-specific risk factors (perceptions of harm; approval of use; and use of each substance by friends and romantic partners). Structural equation models examined non-opioid and opioid-specific associations between latent risk and substance use factors. Opioid misuse and opioid-specific risk factors shared significant variance with latent substance use and latent substance use risk, respectively, which were strongly associated. A statistically significant residual correlation between opioid-specific risk and opioid misuse remained. Young adult opioid misuse reflects a general tendency toward substance use and is strongly predicted by risk for substance use. Opioid-specific risk factors play only a small independent role. Existing evidence-based substance use interventions may be effective in preventing opioid misuse among young adults. •Young adult opioid misuse likely reflects a general tendency to use substances.•Risk for general substance use strongly predicts young adult opioid misuse.•Existing substance use prevention programs may be an efficient & effective strategy for combatting the opioid crisis in young adult populations.