This descriptive, observational pilot study evaluated a smoking cessation intervention using open-label bupropion and nicotine replacement within an addiction treatment center for patients with high rates of comorbid psychiatric diagnoses. Participants were 115 veterans receiving substance abuse treatment at a Veterans Administration outpatient program who voluntarily sought smoking cessation treatment. Three fourths of participants had a psychiatric diagnosis in addition to substance dependence (i.e., dual diagnosis). The intervention consisted of a weekly smoking cessation therapy group and pharmacotherapy as determined by participant and clinician preference (none, nicotine replacement only, bupropion only, or combined nicotine and bupropion). A total of 47 participants (40.9%) completed four group smoking cessation sessions, and 17 (14.8%) completed eight sessions. Of these participants, 27 (23.5%) had breath carbon monoxide (CO) levels <9 ppm (indicating short-term abstinence) at session 4, and nine (7.8%) had CO levels <9 ppm at session 8. Participants who received nicotine replacement alone or with bupropion attended more sessions than did subjects who did not receive nicotine replacement. Participants receiving combined medications had greater reductions in CO levels at session 4 than did the other participants. There was no evidence of increased use of other substances during smoking cessation treatment. These findings indicate that many dually diagnosed individuals are willing to attempt smoking cessation with appropriate pharmacotherapy and achieve reductions in CO measures, but only minimal success was observed with respect to cessation. Additional research is needed to assess medication effects in randomized trials, to explore effects of more intensive treatments, and to assess possible harm reduction from smoking interventions within this population.