Primary immunodeficiency diseases (PIDs) consist of a heterogeneous group of genetically disorders that affect distinct components of the immune system. They manifest as increased susceptibility to life-threatening infections, as well as autoimmunity and inflammatory disease. Among them, patients with diseases of immune dysregulation and autoinflammatory disorders are more complicated with autoimmunity. On the other hand, tumor necrosis factor alpha (TNF-α) is one of the major players in the pathogenesis of autoimmunity and inflammation in PID patients. Monoclonal antibodies (mAbs) targeting TNF-α would be a potential approach as a therapeutic tool for these diseases. In the current review, we aimed to highlight the characteristics of TNF-α and its important role in the pathogenesis of related complication in PID diseases. Critical evaluation of the mAbs targeting TNF-α (e.g. infliximab, etanercept, and adalimumab) in various immune-mediated complications in PID diseases will be provided, and finally, their clinical efficacy and safety will be reported.