Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm, the most common clinical manifestations of which include arterial and venous thrombosis, bleeding and vasomotor/microvascular disturbances. Low-dose (81-100 mg) aspirin once daily, which irreversibly inhibits platelet thromboxane A2 (TxA2) production by acetylating cyclo-oxygenase-1, is the recommended treatment for the control of vascular events in all ET risk categories, except patients at very low risk, who need aspirin for treatment of vasomotor/microvascular disturbances only. Simple observation should be preferred over aspirin prophylaxis in low-risk patients with platelet counts >1,000x109/L or harboring CALR mutations. Plain aspirin should be preferred over enteric coated aspirin because some ET patients display poor responsiveness ("resistance") to the latter. When treated with a once daily aspirin regimen, adequate inhibition of platelet TxA2 production (measured as serum thromboxane B2 level) does not persist for 24 h in most patients. This phenomenon is associated with the patients' platelet count and the number (but not the fraction) of circulating immature reticulated platelets with non-acetylated cyclo-oxygenase-1 and is therefore consequent to high platelet production (the hallmark of ET), rather than increased platelet turnover (which is normal in ET). Twice daily aspirin administration overcame this problem and proved safe in small studies. Although additional data on gastrointestinal tolerability will be useful, the twice daily regimen could already be implemented in clinical practice, considering its favorable risk/benefit profile. However, patients whose platelet count has been normalized could still be treated with the once daily regimen, because they would otherwise be unnecessarily exposed to a potential small risk of gastrointestinal discomfort.