We review the clinical and histologic features of 17 patients with cryoglobulinemia and renal disease. Most cases were associated with evidence of hepatitis C virus (HCV), although a significant minority had no evidence of HCV. The most common histologic pattern for renal involvement was membranoproliferative glomerulonephritis, which was seen in both HCV-positive and HVC-negative patients. Clinical presentation was variable, including nephrotic syndrome, unexplained elevations of serum creatinine, acute renal failure, or extrarenal manifestations. All patients had type II or type III cryoglobulins and all had low serum complements at presentation. Liver function abnormalities in HCV-positive patients were mild. No clinical or laboratory features beyond hepatitis serologies were helpful in distinguishing between HCV-positive and HCV-negative patients. All but 1 HCV-positive patient were treated with interferon (IFN) in either standard or high dosage, and this treatment was largely ineffective. Five of 11 HCV-positive patients progressed to renal failure. HCV patients treated with cyclophosphamide did not develop active liver disease. In all HCV-negative patients, renal function stabilized or improved, and 5 of 6 were treated with cyclophosphamide. In our series, there is limited experience with IFN-ribavirin therapy, which was not well tolerated. Renal cryoglobulinemia is an uncommon illness of diverse etiologies and clinical presentations. Morphologic presentation is also varied. IFN alone is often inadequate therapy for HCV-associated cryoglobulinemia. Experience with IFN-ribavirin in this entity is limited, but has shown promise in hepatic disease and has shown efficacy in HCV-associated cryoglobulinemia. Cyclophosphamide is the treatment of choice for HCV-negative patients and can be used safely in most HCV-positive patients if they fail IFN or IFN-ribavirin therapy, or if they require more aggressive therapy during periods of rapid clinical progression.