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Systemic Lupus Erythematosus (SLE) as an autoimmune disorder, is characterized by a profound B cell activation, however, the association of this disease with a monoclonal gammopathy has been infrequently reported, while hypercalcemia is associated with Hypercalcemia-Lymphadenopathy Syndrome (HL-SLE). We report the case of a 45-year-old man, with anemia, hypoalbuminemia, hypergammaglobulinemia, hypercalcemia, and bone marrow infiltrated with plasma cells. He was diagnosed as Monoclonal Gammopathy of Undetermined Significance (MGUS), one year later he attended with erythematous macules on both arms, at this time the electrophoresis reported a polyclonal hypergammaglobulinemia. Immunologic panel reported ANA 1:2560, mitochondrial ANA 1:80, anti-double-stranded DNA IgG 15.3 and hipocomplementemia. We confirmed SLE and treatment was initiated. In our patient we ruled out MGUS, γHCD (γ-heavy-chain disease) and hypercalcemia related to HL-SLE. To our knowledge, the findings of monoclonal gammopathy and hypercalcemia as the onset of SLE have never been reported and the role of clinical laboratory was very important in the approach to establish a definitive diagnosis.