Objective: College students' prescription stimulant and opioid misuse (PSM and POM) share psychosocial risks with other substance use. We sought to extend a prior study of these issues. Methods: National College Health Assessment (2015-2016) participants ages 18-24 years (n = 79,336) reporting 12-month PSM (defined as use of a drug not prescribed to them), 30-day other illicit drug use (non-cannabis), both, or neither, were compared on other substance use, psychopathology, academic adjustment, attention deficit hyperactivity disorder, and chronic pain. Models were repeated for POM. Results: Relative to those who only misused the prescription drug, those who used other illicit drugs had lower odds of chronic pain and academic problems, but higher odds on nearly every other outcome especially if they also misused the prescription drug. Conclusions: Findings suggest PSM and POM are on a continuum of risk shared with illicit drug use, but also are linked to outcomes specific to these drugs' perceived medical purposes.