Essential thrombocytosis (ET) is currently diagnosed by histopathologic assessment of the marrow after exclusion of a secondary cause or another myeloproliferative disorder. To evaluate the potential of more direct diagnostic methods, we compared the frequency and association of several abnormal features characteristic of neoplastic precursors in 32 patients presenting with platelet counts > 500 x 10(9)/l. Assays for erythropoietin (Ep)-independent erythroid progenitors were performed on all patients, determination of the cycling status of circulating progenitors on 27, and assessment of granulocyte clonality on 15. In most, but not all, patients deregulated progenitor turnover. Ep-independent progenitors and clonal granulocytes were concordant findings. The presence of polyclonal granulocytes and lack of evidence of abnormalities in Ep-dependence or progenitor cycling were also concordant findings in most, but not all patients. Thus, normal (i.e. polyclonal) granulocytes may be produced in occasional patients in spite of the presence of a neoplastic clone. Interestingly, one third of patients thought to have ET on the basis of blood and marrow histopathology showed no abnormalities previously associated with neoplastic progenitors. These findings suggest variability in dominance of the neoplastic clone in some ET patients and the potential utility of a multifaceted laboratory approach to investigate the underlying pathology in patients with thrombocytosis.