OBJECTIVES: Compare patient characteristics and frequency of diagnoses between high-cost and non‒high-cost MS patients receiving DMDs. METHODS: MS patients (aged 18–63; ≥1 MS diagnosis claim:ICD-9-CM:340.xx) with ≥1 DMD claim (first claim=index date) and continuous eligibility 12 months pre- and post-index were identified from a random sample of 5 million lives in the IMS LifeLink Plus database from 1/1/2007–6/30/2012. Patients with all-cause total costs (excluding DMD costs) ≥75th percentile were considered high-cost. Diagnoses potentially associated with costs (“condition indicators”) were grouped into three domains: MS-related conditions (e.g., disability), Clinical Classification System (CCS) code categories (e.g., gastrointestinal), Charlson-Deyo comorbidities. Fisher and Wilcoxon tests were used in unadjusted statistical comparisons. Logistic regression was used to evaluate likelihood of being a high-cost patient. Covariates included demographics, condition indicators, dalfampridine use, newly initiating DMDs and adherence. RESULTS: Analysis included 24,815 patients. 75th percentile for high-cost status was $11,740, yielding 6207 high-cost and 18,608 non‒high-cost patients (mean age:46.3 vs 44.2, respectively; p<0.001). In unadjusted analyses, percentage of patients with each condition indicator was statistically significantly higher in the high-cost group (p<0.05). In logistic regression analyses, age and sex were not consistently predictive of being high-cost. High counts of conditions within each domain (e.g., ≥5 MS-related conditions: odds ratio [OR]:5.801; p<0.0001) and selected individual conditions (e.g., disability: OR:1.809; p<0.0001) were associated with significantly higher likelihood of being high-cost. Dalfampridine use, a symptomatic agent, was also significantly associated with being high-cost (OR:5.744–6.062 across specifications; p<0.0001). Conversely, better adherence (medication possession ratio ≥80%) and newly initiating DMDs were associated with lower likelihood of being high-cost (OR:0.570–0.594 and 0.850–0.898 across specifications, respectively; all p<0.01). CONCLUSIONS: MS-related conditions, CCS categories and Charlson-Deyo comorbidities were independently associated with high costs. Interventions targeting individuals affected by key conditions may be important for reducing costs and disease burden.