Chronic Lymphocytic leukemia (CLL) is the most common leukaemia in adults with no cure. CLL is a lymphoproliferative disease compromising immunity and leading to recurrent infections, a major cause of morbidity and mortality. Treatments primarily focus on reducing tumor burden, usually at the expense of immune functions. Improved targeted therapies have emerged such as ibrutinib, inhibiting Bruton's tyrosine kinase (BTK), approved in 2014, which has allowed effective tumor control in patients with poor prognosis CLL. However, the use of ibrutinib is frequently associated with severe side effects and strongly compromises the immunity of patients. We showed that loss of the BAFF receptor TACI in a mouse model of CLL (TCL-1 Tg mice) recapitulates many of the beneficial effects of ibrutinib. We show that ibrutinib inhibits TACI expression in B and CLL cells, suggesting that therapeutic effects of ibrutinib may in part relate to loss of TACI expression. Indeed, similar to patients treated with ibrutinib, TACI-/- TCL-1 Tg mice experienced lymphocytosis, restored immunity, and reduced IL-10 and TNF production. In addition, TACI-/- CLL cells, unlike TACI+/+ CLL expressed low levels PD-L1, suggesting restored immunocompetency. Healthy humans lacking functional TACI have been identified, indicating that loss of human TACI function is not deleterious, unlike BTK inhibition increasing the risk of bleeding, atrial fibrillation and compromising immunity. Together, these observations suggest that targeting TACI may offer therapeutic advantages in specific clinical settings and may emerge as a useful alternative therapy in high risk patients with BTK-mutant CLL, resistant to ibrutinib or fighting severe infections, hence in need of an intercalated treatment to restore immunocompetency.