© 2017 Taylor & Francis Group, LLC. Background: Since the early 1990s, the United States has seen a significant increase in the prevalence of prescription opioid misuse. Despite benefits prescription opioids provide, misuse can be fatal. Objectives: The current study was designed to investigate the prevalence of prescription opioid misuse, perceived harm of misuse, and reasons for misuse for physical or emotional pain instead of seeking professional medical or mental health treatment. Methods: Survey data were collected in the fall of 2013 via an online survey to a random sample of 668 students from a public Midwestern university. Results: Lifetime prevalence of prescription opioid misuse was 9.5%. Misusers of prescription opioid drugs generally reported lower ratings of perceived harm as compared to individuals not reporting misuse of prescription opioid drugs. Primary reasons for misuse of prescription opioid drugs was to relieve pain (33.9%), “to feel good/get high” (23.2%) and experimentation (21.4%). Lifetime misuse of a prescription opioid drug for physical or emotional pain was reported by 8.1% and 2.2% of respondents, respectively. Primary reasons for misuse for physical pain included because pain was temporary, immediate relief was needed, and no health insurance/financial resources. Primary reasons for misuse for emotional pain included not wanting others to find out, embarrassment and fear. Conclusions/Importance: Reasons for misuse of prescription opioid drugs vary by type of prescription opioid drug. Reasons for not seeking treatment that ultimately lead to misuse, vary by type of pain being treated and may be important considerations in the effort to stem the misuse of prescription opioid drugs among college students.