Fatigue is a prevalent symptom in people with multiple sclerosis (MS), significantly impacting quality of life and daily functioning(1). The Mediterranean diet, with its anti-inflammatory and neuroprotective properties, may help to alleviate fatigue(2). However, existing evidence linking the Mediterranean diet to fatigue in people with MS is primarily cross-sectional, providing limited insights into long-term effects(3). This study aimed to prospectively test associations between the alternate Mediterranean diet score (aMED) and fatigue using data from the United Kingdom (UK) Multiple Sclerosis Register. Dietary intake was measured in 2016 (n = 2,455) and 2022 (n = 3,740) using the EPIC-Norfolk 130-item Food Frequency Questionnaire. A total of 879 participants provided dietary intake data at both timepoints. aMED is a score ranging from 0 to 9, with higher scores indicating greater adherence to a Mediterranean diet (higher consumption of vegetables, fruit, nuts, legumes, whole-grains, fish; greater monounsaturated-to-saturated fat ratio; lower consumption of red meat; moderate consumption of alcohol). Fatigue was measured using the Fatigue Severity Scale (FSS), a 9-item questionnaire that evaluates the extent to which fatigue interferes with daily activities, with scores ranging from 1 to 7. Additionally, fatigue levels were categorised as either ‘high’ (FSS score: ≥ 5) or ‘low’ (FSS score: < 5). The association between aMED and fatigue over six years (from 2016 to 2022) was assessed using generalized mixed-effects models for the continuous FSS score, while mixed-effects logistic regression models were employed to examine the association between aMED and binary FSS categories (high/low). The models were adjusted for age, sex, MS type (benign, relapse-remitting, secondary progressive, primary progressive, unknown), and total energy intake (kcal/day). Analysis was restricted to those participating at both timepoints and who had complete data on diet, covariates, and FSS (n = 379). The study population consisted of 71.5% females, with a mean age of 55.0 years (standard deviation, 9.9). Higher aMED scores (one-unit increase) were significantly associated with lower FSS scores (adjusted β = -0.08; 95% CI: -0.14, -0.03; p = 0.004) and with 17% lower odds of having high fatigue (FSS > 5), with an adjusted odds ratio of 0.83 (95% CI: 0.71, 0.98; p = 0.029). These findings suggest that adherence to a Mediterranean diet may play a protective role in reducing fatigue severity in people with MS over a 6-year period. Further research could explore associations between a Mediterranean diet and other MS related outcomes in this study population.