The pattern of response to Epstein-Barr virus (EBV) has been investigated in 17 patients with essential mixed cryoglobulinemia (EMC) and in 17 control subjects. All subjects in both groups had IgG to the viral capsid antigen at comparable titers. In the absence of signs of recent infection, 13 patients had IgM to viral capsid antigen and 5 had also IgA, while all the controls were negative. EBV genome was present in bone marrow lymphocytes obtained from 4 patients with type II EMC, but not in those of one patient with type III disease; the latter patient's lymphocytes also failed to produce detectable levels of rheumatoid factor in culture, while the other four patients' lymphocytes released high amounts in culture supernatants. These data support the evidence of an association between type II EMC and persistent EBV infection.