The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (encoded by PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of CSK with systemic lupus erythematosus (SLE) and refined its location to the intronic polymorphism rs34933034 (odds ratio (OR) = 1.32; P = 1.04 × 10-9). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, there is increased B-cell receptor (BCR)-mediated activation of mature B cells, as well as higher concentrations of plasma immunoglobulin M (IgM), relative to individuals with the non-risk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points in B cells. © 2012 Nature America, Inc. All rights reserved.