The information provided by a person with multiple sclerosis (MS) may anticipate changes in the course of the disease. To explore the role of a set of standardized patient-reported outcomes (PRO) in predicting disability progression in MS an observational study was conducted in two cohorts of 30 and 86 persons with progressive MS (pwPMS) and relapsing MS (pwRMS), respectively. The associations between baseline clinical, biochemical variables and results on MS quality of life scale (MusiQol), Modified Fatigue Impact Scale (MFIS) and Beck Depression Inventory II (BDI-II) were analyzed. The progression of disability after 2 years of follow-up in pwRMS was investigated. We show that PRO differentiated pwRMS and pwPMS cohorts with lower MusiQoL and higher MFIS and BDI-II scores in the latter. Only MFIS was correlated with disability in pwRMS and high scores in the physical MFIS domain associated with worse performance in 9HPT, and a trend in T25FW and SDMT. Instead, the cognitive MFIS domain was correlated with CHI3L1 in cerebrospinal fluid, a biomarker of progression. At the end of the study, global MFIS and BDI-II were found to be independent risk factors for disability independent of relapse. Although all PRO measures explored were altered in pwPMS, baseline MFIS discriminated current and prospective disability in pwRMS, identifying patients at risk of progression.