CD24 is a cell-surface protein mainly expressed in cells of the immune and central nervous system (CNS), cells that play a critical role in the development of multiple sclerosis (MS). In the current study, we investigated four polymorphisms of the CD24 gene regarding their associations with MS. To this end, univariate and multivariate meta-analysis were applied along with modifications to include data from family-trios so as to increase the robustness of the meta-analysis. We found that the polymorphism 226 C>T (Ala57Val) of the CD24 gene is associated with MS according to the recessive mode of inheritance (odds ratio = 1.75; 95% CI: 1.09, 2.81). Moreover, the 1527-1528 TG>del polymorphism is inversely associated with MS according to the dominant mode of inheritance (odds ratio = 0.57; 95% CI 0.39, 0.83). Conversely, the 1056 A>G and 1626 A>G polymorphisms were not found to be associated with MS. We conclude that the CD24 226 C>T polymorphism increases the risk of MS, while the 1527-1528 TG>del polymorphism seems to have a protective role against MS, suggesting that these two polymorphisms can be used as predictive biomarkers for MS development.