OBJECTIVE: To evaluate the effectiveness and tolerability of bupropion in adults with Attention-Deficit/Hyperactivity Disorder (ADHD) and comorbid active Substance Use Disorders (SUD). METHODS: This was a six-week open trial of sustained-release (SR) bupropion in adults aged 18 to 55 years diagnosed with both ADHD and SUD. Bupropion-SR was initiated at 100 mg SR and increased weekly to a target dose of 200 mg SR twice daily. Subjects were assessed on multiple outcomes including ADHD, SUD, and adverse effects. All analyses were intent to treat, with last observation carried forward. RESULTS: Thirty-two subjects were treated with bupropion, with nineteen subjects completing the entire protocol (59%). At end point there were clinically significant reductions in the ADHD RS (34.1±8.2 to 19.4±11.4, -43%, t=6.49, p<0.0001) and the Clinical Global Impression (CGI) of ADHD severity (baseline=5.0, endpoint=3.8, -24%, t=6.16, p<0.0001). In contrast, there were clinically negligible effects on the self-report of substance use (p's >0.05) and on the overall CGI of SUD severity (-23%, t=4.95, p<0.0001). CONCLUSIONS: Results from this open trial suggest that in adults with ADHD and SUD, treatment with bupropion-SR is associated with clinically significant reductions in ADHD, but not SUD.