A case of a young girl diagnosed with an antibody deficiency syndrome serves to highlight the role of CD81 in B cell biology. Moreover, this case illustrates a fundamental function of the tetraspanin family, namely their association with partner proteins. Characterization of the patient's B cells revealed lack of surface CD19 although both of her CD19 alleles were normal. Further analysis determined that her antibody deficiency syndrome was due to a mutation in the CD81 gene, which did not enable expression of CD19 on the surface of the patient's B cells. Actually, the partnership of CD81 with CD19 and the dependency of CD19 for its trafficking to the cell surface expression were first documented in CD81-deficient mice. CD81 is a widely expressed protein, yet the mutation in the antibody-deficient patient impaired mostly her B cell function. CD81 is required for multiple normal physiological functions, which have been subverted by major human pathogens, such as hepatitis C virus. However, this review will focus on the function of CD81 in cells of the adaptive immune system. Specifically, it will highlight studies focusing on the different roles of CD81 in B and T cells and on its function in B-T cell interactions.