Of 27 patients with granular lymphocyte-proliferative disorders (GLPD), 18 patients had CD3+ T-cell-lineage GLPD (T-GLPD), and 9 patients had CD3-CD16+ natural killer (NK) cell-lineage GLPD (NK-GLPD). In 9 of the 18 patients with T-GLPD, severe anemia of less than or equal to 7.5 g/dl hemoglobin (mean 5.4 g/dl) and erythroid hypoplasia in the bone marrow developed, while the remaining 9 patients with T-GLPD and 9 patients with NK-GLPD exhibited hemoglobin levels of greater than or equal to 10.0 g/dl, and erythroid hypoplasia was not found. The number of leukocytes, neutrophils, lymphocytes or granular lymphocytes in the peripheral blood, or the percentage of lymphocytes in the bone marrow did not differ significantly between the patients with T-GLPD associated with severe anemia and those with T-GLPD not associated with severe anemia, and the immunophenotypes of peripheral blood mononuclear cells (PBMC) were not significantly different either. However, when non-major histocompatibility complex (MHC)-restricted cytotoxicity was assayed with PBMC, T-GLPD patients with severe anemia and NK-GLPD patients exhibited significantly higher levels of non-MHC-restricted cytotoxicity than T-GLPD patients without severe anemia. Because PBMC obtained from T-GLPD patients with severe anemia were shown not to lyse erythroblasts directly, the possibility that patient PBMC lyse erythroblasts in the bone marrow and thus cause anemia seems unlikely. The pathogenesis of anemia in GLPD was discussed.