||Inherited bone marrow failure syndromes (IBMFS) are characterized by progressive bone marrow failure (BMF) and increased risk of myelodysplastic syndrome (MDS), acute leukemia and solid tumors. Previous studies have reported inconsistent data on the levels of serum immunoglobulins, relative number of lymphocyte subpopulations, and inflammatory cytokines in patients with Fanconi anemia (FA). To systematically investigate these parameters we evaluated immune function in 157 well-characterized individuals: 25 FA patients, 29 FA relatives; 33 DC patients, 38 DC relatives; 22 Diamond-Blackfan anemia (DBA) patients, 10 DBA relatives. We examined immunoglobulin levels, lymphocyte subsets, and serum levels of 18 cytokines, including T-helper (Th1)-type (IL-7, IL-17, IL-12p70, IFN-g, TNF-a, G-CSF, GM-CSF), Th2 type (IL-4, IL-6, IL-10), inflammatory cytokines (IL-1a, IL-1b, IL-8, MIP-1a, MCP-1, IP-10, eotaxin, and RANTES), as well as a hematopoietic marker (FLT3-ligand), using Millipore bead assay kits. We compared patients with the three syndromes with each other and with their respective unaffected relatives. Statistical analyses were performed using Excel, STATA or SAS software; p value ≤ 0.05 was significant. One or more serum immunoglobulins were decreased below the normal range in 5/22 (23%) FA, 4/32 (13%) DC, and in 1/22 (5%) DBA patients vs. none of the relatives. In addition, one or more lymphocyte subsets were abnormally low in 9/10 (90%) FA, 7/26 (27%) DC, and 0/9 DBA patients vs. none of the relatives. In FA, low levels of lymphocytes included CD4 in 4 patients, CD19 in 5, and NK-cells in 5; in DC, the low levels of CD4 in 3 patients, CD8 in 3, CD19 in 4, and NK-cells in 4. In all, 10/22 (45%) FA, 10/32 DC (31%) and 1/22 DBA (5%) patients had low immunoglobulins and/or lymphocyte subsets; FA and DC were similar. Among FA patients, 6/10 with decreased immune parameters had solid tumors vs. 1/12 with no immune abnormalities (p=0.02). In DC, 9/10 patients with immune abnormalities had a severe hematological and/or clinical phenotype vs. 6/22 with normal immune studies (p=0.002).To go beyond clinical immune parameters, we examined the large number of candidate inflammatory and hematopoietic cytokines listed above. Levels of IL-4, IL-7, IL-10 and IL-12p70 were undetectable in most samples and not analyzed further. IFN-g was decreased in all patient groups compared with their relatives, and RANTES was significantly reduced in DC compared with relatives and with FA or DBA patients. Compared with their relatives, FLT-3 was increased in all patient groups, IP-10 was increased in FA and DC, and eotaxin was decreased in DC patients. MIP-1α was higher in FA than in DBA patients. TNF-a, FLT3-ligand, IL-8 and G-CSF were highest in FA patients followed by DC and DBA patients High FLT3-ligand values significantly correlated with multilineage cytopenias in FA and DC, and in those patients with DBA who had anemia and neutropenia. The following cytokines were similar in FA, DC and DBA patients and their relatives: IL-1a, IL-1b, IL-6, GM-CSF, MCP-1, IL-17 and eotaxin. Unadjusted values for all parameters were similar to those following adjustment for age, gender and sample handling methods. In conclusion, we identified significant immunoglobulin and lymphocyte abnormalities in FA and DC, but not in DBA patients, and these correlated with the presence of malignancies or severe aplastic anemia. Except for RANTES, the inflammatory cytokine profile was also similar in patients with FA and DC. This is intriguing, since FA and DC have similar cumulative incidences of BMF and similar types of cancers by age 50. In contrast, several cytokine levels were higher in FA and DC than in DBA, a syndrome with only anemia and a lower incidence of cancer. These abnormalities in immunoglobulins, lymphocyte subsets, and cytokine levels may have prognostic value with regard to disease progression, marrow failure and carcinogenesis.