OBJECTIVES: To compare the differences in health care costs between alcohol or opioid-dependent patients who were treated with pharmacological ('Any Medication') and non-pharmacological substances ('No Medication'). METHODS: A retrospective analysis was conducted using a large U.S. health plan claims database from 2005 to 2009. Continuously eligible patients with at least one claim of alcohol/opioid dependence during the identification period, and an alcohol/opioid use disorder diagnosis during the baseline period were included. Propensity score matching (PSM) was applied to compare the risk-adjusted outcomes between the 'Any Medication' and 'No Medication' cohorts. Baseline differences in age, gender, region, comorbidity scores, socioeconomic status, baseline health care utilization and costs were controlled. RESULTS: During the pre-index period, for both alcohol and opioid dependent patients, those in the 'Any Medication' cohort had more distinct psychiatric diagnoses, and were more likely to have Elixhauser Index Scores of higher than 3, when compared to patients from the 'No Medication' cohort. After adjusting baseline patient and clinical characteristics, 10,376 alcohol-dependent patients were matched from each cohort. Patients who were treated without pharmacological medication had more rehabilitation time, a higher detoxification cost burden ($1,350,000 per 1000 patients), and higher total health care costs, compared to patients who were treated with pharmacological medication. Similarly, there were 6,658 patients from each cohort matched for opioid-dependent patients. Patients in the 'No Medication' cohort incurred higher total health care costs than patients in the 'Any Mediation' cohort ($14,353,000 vs. $ 10,192,000 per 1000 patients) during the post-index period. CONCLUSIONS: After controlling for confounders such as demographic factors, comorbid conditions and baseline health care utilization, we showed that pharmacological medication treatments were associated with lower health care costs than non-pharmacological substance treatment for both alcohol and opioid-dependent patients.