Background: Recently, a polymorphism in the LIGHT gene was shown to increase the risk of multiple sclerosis (MS) in a genome-wide association study (GWAS). Objective: Our aim was to investigate if serum levels of LIGHT were affected by this polymorphism and by the disease itself. Methods: Serum levels of LIGHT were investigated in four cohorts; 1) MS ( n = 159) and controls ( n = 160) in relation to rs1077667 genotype; 2) MS at relapse ( n = 30) vs. healthy controls ( n = 26); 3) MS ( n = 27) vs. other neurological disease (OND, n = 33); and 4) MS patients before and after one year of treatment with natalizumab ( n = 30). Results: Carriers of the GG genotype had the lowest serum levels of LIGHT ( p=0.02). Serum levels of LIGHT were increased in MS at relapse in two separate cohorts: vs. healthy controls ( p=0.00005) and vs. remission ( p=0.00006), other neurological disease (OND) ( p=0.002) and OND with signs of inflammation (iOND; p=0.00005). Furthermore, serum levels of LIGHT were decreased by natalizumab treatment ( p=0.001). Conclusion: Soluble LIGHT is an inhibitor of T-cell activation and GG carriers of rs1077667, with the highest risk for MS, had the lowest serum levels. The increased levels of LIGHT at times of increased MS activity suggest that soluble LIGHT is protective and may act to limit inflammation.