IMPORTANCE: It is not known whether decreases in Schedule II (high abuse potential) vs Schedule IV (lower abuse potential) opioid prescriptions overall and among high-risk patients followed publication of the Centers for Disease Control and Prevention (CDC) opioid prescribing guideline on March 15, 2016. OBJECTIVES: To compare the odds of new Schedule II opioid (codeine, hydrocodone, oxycodone) prescriptions vs Schedule IV opioid (tramadol) prescriptions in the 18-month periods before and after the CDC guideline release to determine whether new prescriptions for Schedule II opioids decreased relative to new prescriptions for tramadol and to assess whether patients with benzodiazepine prescriptions or those with depression, anxiety, or substance use disorders had a greater decrease in receipt of Schedule II vs Schedule IV opioids. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of Optum's deidentified Integrated Claims-Clinical data set for 5 million US adults 18 months before and 18 months after March 15, 2016. Eligible patients were 18 years or older, free of HIV and cancer diagnoses, and had a noncancer painful condition. Patients received new prescriptions for codeine, hydrocodone, oxycodone, or tramadol. Data were analyzed from September 5, 2014, to September 14, 2017. EXPOSURE: The CDC opioid prescribing guideline published on March 15, 2016. MAIN OUTCOMES AND MEASURES: The odds of prescriptions for each Schedule II opioid vs tramadol after guideline publication. RESULTS: Data from 279 435 patients were included in the study. The mean (SD) age of patients was 52.9 (16.5) years; 61% were female and 79.4% were White. The prevalence of new prescriptions for each drug before and after guideline publication was as follows: codeine, 7.1% vs 7.0%; hydrocodone, 47.4% vs 45.6%; oxycodone, 22.4% vs 24.0%; and tramadol, 23.0% vs 23.4%. Overall, the odds of being prescribed hydrocodone or oxycodone vs tramadol significantly decreased after guideline publication (odds ratios, 0.95; 95% CI, 0.91-0.98 and 0.86; 95% CI, 0.82-0.90, respectively). Odds of being prescribed a Schedule II opioid vs tramadol after vs before guideline publication were similar in patients with and without benzodiazepine comedication or psychiatric disorders. CONCLUSIONS AND RELEVANCE: In the 18 months after compared with the 18 months before publication of the CDC prescribing guideline, a 14% decrease in oxycodone prescriptions was observed relative to tramadol. Little change in prescriptions of other Schedule II opioids was observed. Schedule II opioids continue to be prescribed to high-risk patients 18 months after publication of the CDC guideline.