Exposure to environmental mercury (Hg) currently may contribute to immune system dysfunction and autoimmune disease. In this study phosphoproteomic analysis was used to investigate the impact of Hg2+ on a B cell line. Treatments were with 0, 2, 5, 10, 20, 50 and 100 uM Hg2+. 1713 phosphoproteins and 1937 confidently localized phosphorylation sites were identified. 161 phosphoproteins responded to Hg2+ treatment (ANOVA, 10% FDR). Hg2+ at 50 and 100 uM stimulated Tyr phosphorylation on residues in the B-cell receptor complex as well as other systems. At 20 uM and below Hg2+ primarily caused hyperphosphorylation of pSer/Thr residues and affected cytoskeletal systems. Map Kinase 1 was exceptional as it was hyperphosphorylated at Tyr 185 following 20 uM and lower Hg2+ treatments. These results contribute novel insight into the mechanism for immune system disruption by Hg2+.