Fanconi's syndrome (FS) is a disorder of sodium-dependent proximal tubule reabsorption, which may complicate plasma cell disorders producing a free monoclonal light chain (LC). FS often occurs in the setting of smoldering myeloma and features cytoplasmic crystalline inclusions of monoclonal kappa LC in proximal tubular cells and malignant plasma cells. Although the clinical and pathological presentation may vary, including lack of crystal formation, monoclonal kappa LCs that underlie FS show a striking genetic and biochemical homogeneity: they almost always belong to the Vkappa1 subgroup of variability and originate from 2 germline genes, O2/O12 or O8/O18. Their variable domain sequences present unusual hydrophobic residues, responsible for the resistance to proteolysis, which leads to LC accumulation in the endocytic compartment of proximal tubule cells. We report a patient with slowly progressive Waldenstrom's macroglobulinemia and full-blown FS with accumulation of a monoclonal kappa LC within proximal tubules, but no detectable crystalline organization. This LC, which belonged to the unusual Vkappa3 subgroup and derived from the L2/L16 germline gene, showed no common substitution with previously described FS kappaI LC and was sensitive to trypsin digestion. These data show that molecular and biochemical characteristics of kappa LCs in patients with FS are more heterogeneous than initially suspected. Mechanisms other than resistance of LCs to endosomal proteolysis probably are involved in the pathogenesis of FS-associated plasma cell dyscrasias.