BACKGROUND: Multiple sclerosis (MS) is an unpredictable disease that can have physical, psychological, and social impacts, reducing health-related quality of life (HRQoL). OBJECTIVES: To compare the HRQoL in patients initiated on delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) and prior approved interferon β-1a/b or glatiramer acetate (ABCRE) therapies. METHODS: Data were identified from the Adelphi MS Disease Specific Programme, a cross-sectional study of MS patients in five EU countries and the US. Relapsing Remitting MS (RRMS) patients were identified, receiving DMF or ABCRE therapies with treatment duration greater than 12 months. HRQoL was assessed using the Hamburg Quality of Life Questionnaire in MS (HAQUAMS), consisting of five domains (fatigue/thinking, mobility of lower limbs, mobility of upper limbs, social function and mood) in which higher scores indicate poorer HRQoL. Inverse-probability-weighted regression-adjustment estimated average treatment effects (ATEs) on the HAQUAMS across DMF and ABCRE cohorts, utilizing a propensity score generated from age, gender, EDSS score at current treatment initiation, BMI,  duration of current treatment, line of therapy, time since MS diagnosis, and number of comorbid conditions. RESULTS: A total of 252 (29 DMF, 223 ABCRE) patients completed the HAQUAMS questionnaire. The overall HAQUAMS score was significantly lower in DMF patients compared to ABCRE patients (ATE=-0.45, p<0.001, vs. 1.95). Significant differences were observed in four of the five subscales, as follows: fatigue/thinking (ATE=-0.47, p=0.001, vs. 1.90), lower limb mobility (ATE=-0.43, p=0.009, vs. 1.84), social function (ATE=-0.54, p<0.001, vs. 2.05), and mood (ATE=-0.45, p<0.001, vs. 2.40).  The ATE for upper limb mobility score was not statistically significant (ATE=-0.15, p=0.075, vs. 1.38).  CONCLUSIONS: RRMS patients on DMF had significantly better HRQoL as measured by the HAQUAMS, versus RRMS patients on ABCRE therapies.