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The tetraspan molecule CD81 is widely expressed on immune cells, such as B-, T-, NK-lymphocytes, monocytes and eosinophils, but also on most stromal and epithelial cells and on hepatocytes. In B-cells it is a member of the CD19 complex (CD19, CD21, CD81, CD225), which is required for signaling together with the B-cell antigen receptor upon antigen recognition. Its functions on other cells are unclear, but murine studies show an antiproliferative role for CD81. On hepatocytes, two different epitopes of CD81 act as a co-receptor for Hepatitis C virus and for Plasmodium infection. We evaluated a 4-year-old girl from consanguineous parents of Moroccan decent. She presented with recurrent infections and an acute nephrotic syndrome: >50% of glomeruli were affected due to focal mesangial hypercellularity. She showed poor weight gain (below 3rd percentile), but normal motor development. Her spleen and liver were enlarged, but function normally. Measurements of retina epithelium and CNS showed no signs of hypercellularity. Although serum IgG levels were strongly decreased (2.4 g/L) and IgM and IgA concentrations low within normal range, she tested positive for anti-platelet antibodies. Flow cytometric immunophenotyping of blood showed normal distribution and absolute numbers of granulocyte, monocyte and lymphocyte subsets; however, no CD19 expression was detected on the patient’s B-cells, whereas CD21 expression levels were normal. The patient carried no mutations in the CD19 and IFITM1 (CD225) genes. Additional immunophenotyping showed that all cells lacked CD81 expression. Sequencing of the CD81 gene showed a homozygous G>A substitution immediately downstream of exon 6 (c.561+1G>A). Spectratyping and quantitative PCR analysis showed clearly reduced total CD81 mRNA expression levels. Nearly all CD81 transcripts contained 13 additional nucleotides downstream of exon 6. This insertion results in a frame-shift and a premature stop (p.Glu188MetfsX13). The hypothetical protein lacks the fourth transmembrane domain. Similar to previously described CD19-deficient patients, our patient had reduced numbers CD5+ B-cells and Ig class switched and non-switched CD27+ memory-B cells. Whereas Vh-Cα and Vh-Cγ transcripts from Ig switched cells contained somatic hypermutations, the response of the patient’s B cells to in vitro stimulation through the B-cell receptor was impaired. The antibody response to rabies, tetanus and pneumococcal vaccinations is currently under investigation, as well as the potential impact of CD81 deficiency on the antigen-specific Th1 and Th2 cytokine production. In conclusion, the here presented CD81 deficiency is a new primary immunodeficiency, which leads to disruption of the CD19 complex and consequent hypogammaglobulinemia comparable to the CD19 deficiency. However, due to the broad tissue distribution, the clinical phenotype is not restricted to the B-cell system. Other organs are affected as well, most likely due to excessive proliferation and hypercellularity, with acute nephritic syndrome as dominant clinical problem. Currently, in vitro studies are being performed to identify whether the CD81 defect directly results in impaired B-cell and T-cell functions and abnormal proliferation of kidney and liver cells.