Patients with indolent B-cell Non-Hodgkin's lymphomas benefit little from conventional tumor therapies, like chemotherapy and radiotherapy, hence a "watch-and-wait" strategy is often adopted early in their care. Efforts to improve prognosis of these diseases through immunotherapy for more than one decade now have not had significant success to date. CLL patients have an increased rate of infections, and several immune defects have already been detected in them. The M-component of MGUS patients has similarly triggered several investigations of their T-cell compartment. In contrast, patients with non-leukemic indolent B-NHLs, mainly FL and MALT lymphomas, have neither clinically overt immunodeficiency nor impressive serologic abnormalities. Their immune status has thus received little attention. This study aimed to testing the hypothesis that these patients do have subclinical immune abnormalities, which could interfere with the outcome of our immunotherapeutic efforts and influence the natural history of the lymphoma. With an age-matched, retrospective and prospective analysis we show that untreated FL and MALT lymphoma patients have systemic immune activation and decreased peripheral blood CD4 cell counts. Naive CD4 cells are predominantly depleted. CD4 cell proliferation rates and delta-TREC concentrations are only slightly affected, which points to redistribution as the main mechanism for the observed CD4 lymphocytopenia. The chronic immune activation results in an accumulation of prematurely senescent, dysfunctional T cells, an immune constellation that is known to impair responses to vaccination even in healthy subjects. The peripheral blood CD4 cell Vbeta repertoire is skewed in the case of MALT, but not in the case of Follicular Lymphoma. Functional CD4 cell studies reveal two distinct patterns of aberration: first, hyperreactivity and Th2 shift, both associated with the degree of in vivo immune activation; second, a stage-dependent impairment of TCR-signaling. We conclude that despite focal pathology non-leukemic indolent B-NHLs are associated with systemic immunologic derangement. Since FL and MALT lymphoma lesions are rich in recently activated CD4 cells, we postulate that the origin of immune dysregulation in these diseases is the tumor itself. Furthermore, we show that the earliest immune system abnormalities in untreated CLL are a redistribution of T cells to the circulation, chronic activation of the CD8 cell compartment and an even more severe form of the TCR-signaling impairment encountered in advanced stage non-leukemic indolent B-NHLs. With regards to MGUS, our findings indicate that CD4 cell compartment abnormalities in these patients are minimal, in accordance with already published data.