The lack of diagnostic certainty in some patients makes it difficult to distinguish between primary and secondary forms of thrombocytosis. To augment current diagnostic studies for thrombocytosis, we retrospectively evaluated clinical records and bone marrow trephine specimens of 183 patients with thrombocytosis-164 with essential thrombocythemia (ET), 19 with reactive thrombocytosis (RT)-for bone marrow angiogenesis, bone marrow megakaryocyte c-Mpl staining, and morphologic evidence of megakaryocyte proliferation. Angiogenesis was increased in patients with ET compared with healthy controls (P <.0001) and patients with RT (P =.006). In addition, an increase in angiogenesis was associated with certain disease features such as splenomegaly (P =.004) and reticulin fibrosis (P =.005). Decreased megakaryocyte c-Mpl staining was observed in a heterogeneous pattern in ET compared with healthy controls (P <.0001) and RT (P <.0001). Histologic stratifying criteria incorporating increased angiogenesis, decreased megakaryocyte c-Mpl expression, and marked megakaryocyte proliferation in the bone marrow was highly sensitive (97%) and specific (95%) for distinguishing ET from RT (P <.0001). However, with the current duration of follow-up available on the patients, none of the histologic features evaluated have yet demonstrated prognostic value for subsequent clinical course, vascular events, or survival.