As cryoprecipitation is a laboratory artifact, it is necessary to identify those patients with mixed cryoglobulinemia who actually have the cryoglobulinemic syndrome. In certain cases, although by no means frequently, mixed cryoglobulins are associated with a vasculitis that produces a spectrum of manifestations resembling those of experimental serum sickness. Therefore, we propose a set of criteria to be used as the starting point for establishing a definitive diagnosis. The next step in the classification of cryoglobulinemic syndromes is to define the primary or secondary nature of the disease process and the mono- or polyclonal nature of the rheumatoid factor. Finally, the extent of the vasculitis must be assessed by screening for liver and renal involvement and peripheral neuropathy. Despite the high prevalence of HCV markers in both the primary and secondary forms, we believe our classification is useful for characterizing groups of patients with different diseases and different prognoses.