Arginine methylation catalyzed by protein arginine methyltransferases (PRMT) is a common post-translational modification in mammalian cells, regulating many important functions. PRMT1 is known to regulate signalling from the B-cell receptor (BCR), controlling the balance between proliferation and differentiation early in development. We show that PRMT1 is expressed in mouse and human peripheral B cells and increases in amount and activity on activation, both in vitro and in vivo. Conditional deletion of the Prmt1 gene in mature B cells established that while B cell subsets in the periphery appeared normal, in vivo immune responses were abolished. In vitro activation of Prmt1-/- B cells through the BCR revealed diminished proliferation and survival, which correlated with altered signal transduction. Thus, atypical arginine methylation arising from unbalanced PRMT1 activity impacts on multiple cellular processes required for normal humoral immunity.