B cell chronic lymphocytic leukemia (B-CLL) is the most frequent hematological neoplasm in the human adult life. This tumor is often associated with hypogammaglobulinemia and infections. This review focuses on recently reported mechanisms underlying the humoral immunodeficiency occurring in B-CLL. Tumoral cells provoke several alterations to normal regulatory T cells, which, in turn, can impair the correct maturation of B cells. In addition, the direct inhibitory effect of B-CLL cells on immunoglobulin (Ig)-secreting plasma cells (PC) may account for the humoral immunodeficiency. This phenomenon is mediated by the interaction of CD95L molecules expressed by B-CLL cells with the death receptor CD95 that is up-regulated on patients' PC, leading to PC apoptosis and subsequently to hypogammaglobulinemia. Furthermore, the presence of CD95L on B-CLL cells could play an additional role in tumoral immune-escape, as reported in other neoplasms.