Background: There is accumulating data suggesting an association between serum lipids, apolipoproteins and disability in multiple sclerosis (MS). Objectives: To investigate the associations between serum lipids, apolipoproteins and disability in MS. Methods: A cohort of 178 participants with clinically-definite MS in southern Tasmania, Australia were prospectively followed from 2002 – 2005, and serum samples were obtained at study entry and at each biannual review, to measure lipid profile and apolipoprotein levels. Associations with disability and annual change in disability were evaluated using linear regression and multilevel mixed-effects linear regression. Results: In the unadjusted analyses, nearly all lipid-related variables were positively associated with Expanded Disability Status Scale (EDSS). After adjustment for confounders, total cholesterol (TC) ( p = 0.037), apolipoprotein B (ApoB) ( p = 0.003), and the apolipoprotein B to apolipoprotein A-I ratio (ApoB/ApoA-I ratio) ( p = 0.018) were independently associated with a higher EDSS. Higher body mass index (BMI) was also independently associated with higher EDSS ( p = 0.013). With the progression analysis, the total cholesterol to high density lipoprotein (HDL) ratio (TC/HDL ratio) ( p = 0.029) was prospectively associated with subsequent change in EDSS. Conclusion: In this prospective population-based cohort study, an adverse lipid profile was associated with high levels of MS disability and disease progression. Improving serum lipids may be beneficial for MS patients, to potentially improve clinical outcomes and vascular comorbidities.