Multiple myeloma (MM) is a very heterogeneous hematological malignancy characterized by the proliferation of clonal plasma cells in bone marrow, leading to a decrease in normal plasma cells. The immune system plays a key role in both the pathogenesis and the prognosis of MM. A wide range of immune dysfunctions can be demonstrated in most patients at diagnosis. The presence of suppression of uninvolved immunoglobulins, also called classical immunoparesis (CIP), can be demonstrated in the majority of newly diagnosed MM (NDMM) patients, although its prognostic impact remains controversial in previous studies. Our population-based study confirms that CIP is present in most NDMM patients. It is associated with several well-known prognostic factors, including the International Staging System, being more frequent in late stages. Median overall survival in CIP+ patients was 62.4 months (CI 95%, 52.1-72.7), whereas it was not reached for those CIP-(p=0.150). Despite the absence of statistical significance, the multivariate Cox proportional hazards model endorses CIP as an independent and strong prognostic factor for overall survival in NDMM, besides age, performance status, total serum cholesterol, and the presence of 1q gain. More comprehensive studies, including complete immune profiling, are warranted to establish the role of CIP in the context of the current and emerging prognostic factors in NDMM.