This study presents a comprehensive analysis of 1000 patients with essential thrombocythemia (ET) seen at the Mayo Clinic between 1967 and 2023. The median age of the patients was 58 years, with a female predominance (63%). The most common driver mutations were JAK2 (62%), CALR (27%), MPL (3%), and triple-negative (TN) (8%). Patients with JAK2 mutations were older (median 71 years), while those with CALR mutations were younger (median 52 years). Female gender was more common in TN and JAK2-mutated cases. Extreme thrombocytosis (ExT) was more frequent in CALR-mutated cases, and leukocytosis was more common in JAK2-mutated cases. In multivariable analysis, risk factors for overall survival included older age, male gender, absolute neutrophil count (ANC) ≥ 8 × 10^9/L, absolute lymphocyte count (ALC) < 1.7 × 10^9/L, hypertension, and arterial thrombosis history. For leukemia-free survival, ExT and abnormal karyotype were significant risk factors. For myelofibrosis-free survival, ANC ≥ 8 × 10^9/L 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 was found to reduce the risk of both arterial and venous thrombosis. The study also developed risk models for overall survival, leukemia-free survival, myelofibrosis-free survival, and thrombosis-free survival, providing valuable prognostic information for patient management and future clinical trials.This study presents a comprehensive analysis of 1000 patients with essential thrombocythemia (ET) seen at the Mayo Clinic between 1967 and 2023. The median age of the patients was 58 years, with a female predominance (63%). The most common driver mutations were JAK2 (62%), CALR (27%), MPL (3%), and triple-negative (TN) (8%). Patients with JAK2 mutations were older (median 71 years), while those with CALR mutations were younger (median 52 years). Female gender was more common in TN and JAK2-mutated cases. Extreme thrombocytosis (ExT) was more frequent in CALR-mutated cases, and leukocytosis was more common in JAK2-mutated cases. In multivariable analysis, risk factors for overall survival included older age, male gender, absolute neutrophil count (ANC) ≥ 8 × 10^9/L, absolute lymphocyte count (ALC) < 1.7 × 10^9/L, hypertension, and arterial thrombosis history. For leukemia-free survival, ExT and abnormal karyotype were significant risk factors. For myelofibrosis-free survival, ANC ≥ 8 × 10^9/L 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 was found to reduce the risk of both arterial and venous thrombosis. The study also developed risk models for overall survival, leukemia-free survival, myelofibrosis-free survival, and thrombosis-free survival, providing valuable prognostic information for patient management and future clinical trials.