INTRODUCTION: Knowledge of which factors are determinant of quality of life (QoL) in patients with multiple scleroris (MS) would assist clinicians in choosing the most appropriate interventions. The aim of this study was to determine the contribution of sociodemographic and clinical factors in the predicting QoL in a 2-year cohort of patients with relapsing-remitting MS (RR-MS). METHODS: The study had a multi-center, multi-regional, and longitudinal design. Main inclusion criteria were: patient with a RR-MS subtype (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score lower than 7.0. Sociodemographic (age, gender, education level, marital and employment status) and clinical (disability, disease duration, relapse) data were recorded. The QoL was assessed using the MusiQoL (disease-specific) and SF-36 (generic) questionnaires. Each patient was investigated at baseline and 24 months post-inclusion (ClinicalTrials.gov identifier: NCT00702065). RESULTS: Five hundred and twenty-six patients were enrolled in the present study. The 24-month MusiQoL index score was significantly inversely correlated with the disease duration. Baseline EDSS score impacted in both 'physical-like' and 'psychological-like' dimensions. At least one relapse during the follow-up period was associated with lower physical scores. Occupational status and marital status were associated with 24-month scores of MusiQoL and SF-36. CONCLUSION: After adjusting for disability and relapse occurrence, sociodemographics (age, marital status, and occupational status) and baseline QoL scores were also independent QoL predictors in MS patients. Special attention should be given to subgroups to ensure optimal management.