<p>Monoclonal gammopathies (MGs) have been associated with dysfunction of the innate immune system, and specific autoinflammatory disorders have been defined by the presence of monoclonal immunoglobulins. MGs of clinical significance (MGCS) are characterized by paraprotein-mediated tissue damage and organ dysfunction. Most cases of MGCS are related IgM-associated disorders. In this review, we aim to describe this group of disorders – known as MGs of inflammatory significance (MGIS) or autoinflammatory gammopathies – according to their clinical phenotypes. MGIS remains a proposed concept that lacks validation in prospective studies but should be suspected whenever MG are accompanied by specific clinical manifestations such as peripheral neuropathy, neutrophilic dermatosis, fever and/or elevation of acute-phase reactants. MGIS frequently affect the kidneys, peripheral nervous system, and skin. Beyond the standard diagnostic workup for MGs (e.g., complete blood count, serum calcium and creatinine levels, serum protein electrophoresis and immunofixation), the measurement of acute-phase reactants, VEGF, and erythropoietin levels may be valuable for the diagnosis of autoinflammatory gammopathies. The management of these disorders should address not only the proliferative clone but also the autoinflammatory component of the disease. In Schnitzler syndrome and related conditions, treatment is most effective when based on IL-1 inhibition, whereas VEXAS syndrome generally responds best to corticosteroids as the primary therapeutic strategy. For disorders such as POEMS and TEMPI syndromes, therapies that directly target and eradicate MG have demonstrated the greatest benefit.</p>