Objective-The majority of cigarette smokers have a lifetime diagnosis of substance abuse and/or mental illness, and treatment outcomes for smokers with these comorbidities are generally reported to be worse than for smokers without co-morbidities. We sought to examine the effect of specific substance abuse/mental illness diagnoses compared to one another on treatment outcomes.Method-A retrospective chart review of naturalistic treatment for Tobacco Dependence was performed on male smokers (n= 231) who enrolled in the Greater Los Angeles Veterans Affairs Mental Health Clinic Smoking Cessation Program over a 1.5 year period. Subjects in this program underwent comprehensive treatment for Tobacco Dependence (including, but not limited to, group psychotherapy, nicotine replacement therapy, and bupropion HCl). Quitting smoking was defined as a report of at least 1 week of abstinence and an exhaled carbon monoxide less than 8 parts per million at the final clinic visit.Results-Of the total group, 36.4% (84/231) quit smoking at the end of treatment. Quit rates were affected by the presence of specific diagnoses, with smokers with a history of Alcohol Abuse/ Dependence or Schizophrenia/Schizoaffective Disorder having poorer response rates than smokers without such diagnoses. Other substance abuse and mental illness diagnoses did not affect quit rates.Conclusion-Lower quit rates among patients with Alcohol Abuse/Dependence or Schizophrenia/ Schizoaffective Disorder may be due to the severity of these conditions, and suggests that specialized treatment is needed for these populations of smokers. Smokers with most co-morbid diagnoses are successfully treated with standard treatment methods.