BACKGROUND: Patients often misuse a combination of prescription drugs including opioids; however, the relationship between a controlled substance (CS) score and health outcomes is unknown. OBJECTIVE: To examine the association between a CS scoring algorithm and health care use, specifically total cost of care, hospitalizations, and emergency room (ER) visits. METHODS: This analysis was a retrospective cohort study using administrative claims data from a large U.S. health insurer. Included in the analysis were 999,852 members with a minimum CS score of 2.5 in the fourth quarter (4Q) of 2012, who were continuously enrolled from January 1, 2012, to December 31, 2013, and who were aged 18 years or older. A CS score was calculated using 4Q 2012 (3 months) prescription claims data and divided into 3 components: (1) number of CS claims, (2) number of unique pharmacies and unique prescribers, and (3) evidence of increasing CS use. The primary outcomes were total cost of care (pharmacy and medical costs), all-cause hospitalizations, and ER visits in 2013. We also quantified what a 1-point change in CS score meant for the primary outcomes. RESULTS: 47[%] of members had a CS score of 2.5, indicating a single CS claim, and 51[%] of members had a score between 3 and less than 12. The remaining 2[%] (20,858 members) had a score of 12 or more. There was a statistically significant and consistently increasing association between the 4Q 2012 CS score and hospitalizations, ER visits, and total costs of care in 2013. A 1-point change in CS score was associated with a $1,488 change in total cost of care, 0.9[%] change in the hospitalization rate, and 1.5[%] change in the ER visit rate. CONCLUSIONS: There is a linear association between increasing CS score and negative health outcomes. Insurers should consider interventions to lower member CS scores.