To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13–14 (rs703842, P = 5.4 times 10⁻¹¹; rs10876994, P = 2.7 times 10⁻¹⁰; rs12368653, P = 1.0 times 10⁻⁷) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 times 10⁻⁷; rs1569723, P = 2.9 times 10⁻⁷). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 times 10⁻¹⁸⁴; CD58, P = 9.6 times 10⁻⁸; EVI5-RPL5, P = 2.5 times 10⁻⁶; IL2RA, P = 7.4 times 10⁻⁶; CLEC16A, P = 1.1 times 10⁻⁴; IL7R, P = 1.3 times 10⁻³; TYK2, P = 3.5 times 10⁻³) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).