A study of 1000 patients with essential thrombocythemia (ET) at the Mayo Clinic between 1967 and 2023 reveals key clinical and prognostic characteristics. The median age was 58 years, with 63% female. JAK2, CALR, and MPL mutations were present in 62%, 27%, and 3% of patients, respectively, while 8% were triple-negative (TN). Excessive thrombocytosis (≥1000 × 10⁹/L) was present in 26%, and leukocytosis (>11 × 10⁹/L) in 20%. Abnormal karyotype was present in 6% of patients. JAK2-mutated patients were older, while CALR and TN patients were younger. Female gender was more common in JAK2 and TN cases than in CALR/MPL cases. Excessive thrombocytosis was associated with CALR mutations, while leukocytosis was linked to JAK2 mutations. Risk factors for overall survival included older age, male gender, high absolute neutrophil count (ANC), low absolute lymphocyte count (ALC), hypertension, and arterial thrombosis history. For leukemia-free survival, excessive thrombocytosis and abnormal karyotype were significant risk factors. For myelofibrosis-free survival, high ANC and MPL mutation were significant. For arterial thrombosis-free survival, age ≥60 years, male gender, arterial thrombosis history, hypertension, and JAK2 mutation were significant. For venous thrombosis-free survival, male gender and venous thrombosis history were significant. Aspirin therapy reduced both arterial and venous thrombosis risk. Risk models based on hazard ratios showed varying survival outcomes. The study confirms the role of driver mutations in ET prognosis and highlights the importance of risk stratification for treatment decisions. The findings provide valuable insights into the natural history and management of ET.A study of 1000 patients with essential thrombocythemia (ET) at the Mayo Clinic between 1967 and 2023 reveals key clinical and prognostic characteristics. The median age was 58 years, with 63% female. JAK2, CALR, and MPL mutations were present in 62%, 27%, and 3% of patients, respectively, while 8% were triple-negative (TN). Excessive thrombocytosis (≥1000 × 10⁹/L) was present in 26%, and leukocytosis (>11 × 10⁹/L) in 20%. Abnormal karyotype was present in 6% of patients. JAK2-mutated patients were older, while CALR and TN patients were younger. Female gender was more common in JAK2 and TN cases than in CALR/MPL cases. Excessive thrombocytosis was associated with CALR mutations, while leukocytosis was linked to JAK2 mutations. Risk factors for overall survival included older age, male gender, high absolute neutrophil count (ANC), low absolute lymphocyte count (ALC), hypertension, and arterial thrombosis history. For leukemia-free survival, excessive thrombocytosis and abnormal karyotype were significant risk factors. For myelofibrosis-free survival, high ANC and MPL mutation were significant. For arterial thrombosis-free survival, age ≥60 years, male gender, arterial thrombosis history, hypertension, and JAK2 mutation were significant. For venous thrombosis-free survival, male gender and venous thrombosis history were significant. Aspirin therapy reduced both arterial and venous thrombosis risk. Risk models based on hazard ratios showed varying survival outcomes. The study confirms the role of driver mutations in ET prognosis and highlights the importance of risk stratification for treatment decisions. The findings provide valuable insights into the natural history and management of ET.