Hepatitis C virus (HCV) infection represents, by far, the major cause of mixed cryoglobulinemia (MC). The renal disease associated with this pathological condition is now well described. By contrast, renal involvement in patients with MC not associated with HCV has been only poorly described, and few cases have been reported. We analyzed the demographic, clinical, and laboratory features and outcome in patients presenting with renal disease associated with MC not related to HCV infection. Records of 20 patients with MC and renal disease, with no evidence of HCV by serology and polymerase chain reaction analysis, were retrospectively analyzed. Renal biopsies and extensive searches for lymphoproliferative disorder were performed in all patients at presentation. MC was related to primary Sjögren Syndrome (pSS) in 9 patients, and to non-Hodgkin lymphoma in 1 patient, while MC was classified as essential in the remaining 10 cases. Renal involvement was characterized by microscopic hematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85% of patients (mean glomerular filtration rate, 46 mL/min per 1.73 m). Membranoproliferative glomerulonephritis with subendothelial deposits was observed in all kidney specimens. Skin vasculitis was the main extrarenal manifestation. In all patients, cryoglobulinemia was classified as type II MC, characterized by monoclonal IgMkappa and polyclonal IgG. Most patients (17/20) were treated with steroids or immunosuppressive agents, or both. Initial renal remission was observed in 94% of patients. However, renal relapse occurred in most patients, with 10% reaching end-stage renal disease. Three patients with essential MC developed B-cell lymphoma 36-48 months after the diagnosis of MC. Unexpectedly, B-cell lymphoma induced by Epstein-Barr virus infection occurred in only 1 of the 9 pSS patients. Forty percent of patients died as a result of extrarenal causes.Renal disease associated with MC unrelated to HCV is characterized by the high prevalence of pSS (45%), the finding of CD20+ B-lymphocyte nodular infiltrates in the kidney interstitium, and a high incidence of overt B-cell lymphoma during follow-up. These findings emphasize the need for repetitive clinical evaluation in those patients.