Background and Objectives Opioid use disorder among young adults is rising sharply with an increase in morbidity and mortality. This study examined differences in treatment response to a fixed dose of buprenorphine-naloxone between heroin (HU) and prescriptions opioids (POU) users. Methods 80 opioid dependent young adults (M = 22 years) were treated with buprenorphine-naloxone 16-4mg/day for 8 weeks. Differences between HU (N = 17) and POU (N = 63) on changes in weekly opioid use, opioid craving, withdrawal and depression symptoms were analyzed with mixed-effects regression models. Results The HU had an overall mean proportion of weekly opioid use of 0.32 (SD = 0.14) compared to POU’s weekly mean of 0.24 (SD = 0.15) showing a significant main effect (Z = 2.21, p = 0.02). Depressive symptoms (CES-D scores) were elevated at baseline for both groups (HU: M = 23.1, SD = 11.9; PO: M = 22.2, SD = 9.4), but only POU improved significantly to a score of 9.88 (SD = 7.4) compared to HU’s score of 18.58 (SD = 10.3) at week 8 (Z = 2.24, p = 0.02). There were no significant differences in treatment retention, craving or withdrawal symptoms. Discussion and Conclusions Treatment response to 16-4mg/day of buprenorphine-naloxone was significantly diminished for heroin users relative to opioid prescription users in weekly opioid use. Heroin users also had persistent depressive symptoms suggesting the need for close monitoring. Scientific Significance These data suggest that young heroin users might require higher doses of buprenorphine.