Twelve patients with clinical and laboratory findings typical of essential mixed cryoglobulinemia, type II (EMC II) underwent multiple liver and bone marrow biopsies. In 9 of 12 cases (all hepatitis B surface antibody-negative), routine histology revealed patent infiltration of liver portal tracts, lobules and sinusoids by small lymphocytes provided with cytological characteristics closely resembling those of the LP immunocytoma of the Kiel classification. At immunophenotyping on frozen sections, these elements expressed the CD22 antigen (marker of B cells) and bore the same type of immunoglobulin (IgM/k = 8, IgM/lambda = 1) as the monotypic component in the serum. Furthermore, in 7 of 9 patients repeated bone marrow needle biopsies showed multiple foci of infiltration by plasmacytoid cells, often with paratrabecular location. In the remaining 3 cases (all hepatitis B surface and core antigen-positive), liver biopsies were consistent with a diagnosis of cirrhosis (two) or chronic active hepatitis (one). In two of them, however, Jamshidi needle biopsy evidenced bone marrow infiltrates quite similar to those observed in the other group. On the basis of these findings, the authors discuss the hypothesis that most EMC II are substained by a low-grade malignant lymphoma.