Cyclic oscillations in the peripheral blood platelet count were recently described in two patients with polycythemia vera (PV) receiving therapy with hydroxyurea (HU). This phenomenon can make proper HU dosing very challenging and may be especially problematic in PV patients who are at risk for thrombohernorrhagic complications. In this report, we describe four new cases of HU-associated platelet oscillations in patients with PV and extend our observations on one of the two previously reported cases. We also review cyclic thrombocytosis within the broader context of periodic hematopoiesis. A thrombopoietin-mediated negative feedback loop is central to most models of periodic thrombopoiesis, but this is probably an oversimplification. It is possible that HU destabilizes the delicate balance of thrombopoietin/c-Mpl signaling in megakaryocytic lineage hematopoiesis that is already markedly altered in PV; this hypothesis remains speculative. For patients who develop oscillatory variation in their platelet counts associated with HU use, keeping the HU dose constant may result in damping or termination of the cycles. However, this strategy is not always successful.