Background: Evidence is needed that adherence to disease-modifying therapies (DMT) for multiple sclerosis (MS) can reduce total medical costs or hospitalization events, by use of Pharmacy Quality Alliance (PQA) approved methods. Objectives: To identify significant associations between DMT medication adherence and total medical (i.e., inpatient and outpatient) cost, MS medical costs, hospitalization and length of stay (LOS) over a 2-year period. Methods: We used a retrospective cohort design with commercially-insured patients from the MarketScan Commercial Claims and Encounters database from 2015–2017. DMT adherence was calculated with proportion of days covered (PDC) using PQA criteria for non-infused DMTs. Selected patients had DMT fills starting Jan 2015 (with 2-year follow-up through Dec 2017 from index), continuously enrolled, and no indication of death or hospice stay. MS patients were categorized as consistently adherent (PDC ? 80%) in both years (2), adherent only in one year (1), or adherent in neither year (0). Outcomes were combined 2-year totals: medical costs, MS medical costs, pharmacy costs (DMT or associated medication), hospitalizations and LOS. Model covariates were gender, age, census region, metropolitan location, comorbidities, associated MS medication therapy groups, DMT switching, mail order, and changed insurance. Results: Of the 18,507 patients: 60.6% were adherent in both years (group 2), 26.5% were adherent in one year (group 1), and 12.9% were non-adherent in both years (group 0). Adjusted pharmacy costs for DMTs or associated therapies were significantly higher for group 2 vs group 0 (p<.0001). Compared to patients in group 1, those in group 2 had significantly lower total medical costs (-$1,287, p<.02), and significantly lower MS medical costs (-$423, p<.001). In addition, this adherence effect interacted with comorbidity indication, with a larger cost difference for those with at least one comorbidity (total -$2,667, p<.02; MS costs -$848, p<.003). Group 2 had significantly fewer hospitalizations compared to group 0 (p<.0001); with significantly shorter LOS (about 2 fewer days respectively, p<.03). Conclusions: DMT medication adherence (PDC ?80%) can lead to lower medical costs over a two year period, compared to non-adherent cohorts, with a greater cost difference for those with at least one comorbidity. There were significantly fewer rates of hospitalization and shorter days stay for the adherent group compared to the least adherent group.