The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.