Multiple sclerosis (MS) is a chronic inflammatory disease and one of the leading causes of disability in young adults. Functional markers able to predict MS progression are still lacking. It is recognized that olfactory dysfunction may be an early symptom in MS. The aim of this study was to investigate whether alterations in olfactory event-related potentials could play a prognostic role in MS. Thirty patients affected by MS relapsing-remitting underwent an olfactory potential examination (T0). Three years after baseline (T1), 28 of 30 patients were clinically evaluated by expanded disability status scale. In addition, the number of Disease Modifying Therapies (DMTs) and the total number of relapses occurred in the last 3 years were collected. At T1, we observed a negative correlation between presence/absence of olfactory potentials and expanded disability status scale scores (rpb = -0.48; p = 0.009). A significant trend for a negative correlation between presence/absence of olfactory potentials and disease duration (rpb = -0.36; p = 0.06) and total number of relapses (rpb = -0.34; p = 0.08) was found. Only patients with olfactory potential absence showed a significant trend in the difference of the disability status scale (p = 0.06) between T0 and T1. In the sub-group of patients with reduced olfactory potential amplitude, we detected a trend for a negative correlation between the disability status scale and the amplitude of N1-P2 components more marked at T1 (r = -0.52; p = 0.06) than T0 (r = -0.47; p = 0.09). This is the first study that evaluated the prognostic role of olfactory event-related potentials in MS. Our results highlighted that olfactory alterations of MS patients were related to disability progression and, to a lesser extent, disease activity. The analysis of olfactory potential parameters confirmed the involvement in olfactory network damage of inflammatory and/or neurodegeneration processes which could predict the progressive course of the disease.