This study presents a comprehensive analysis of 1000 patients with essential thrombocythemia (ET) seen at the Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM) in Florence, Italy, between 1980 and 2023. The median age of the patients was 59 years, with a higher proportion of females (65%). The most common mutations were JAK2 (66%), CALR (19%), and MPL (4%), with 11% being triple-negative (TN). Key findings include: - **Clinical and Laboratory Features**: 16% had extreme thrombocytosis (platelets ≥1000 × 10^9/L), 16% had leukocytosis (leukocytes >11 × 10^9/L), and 52% had at least one cardiovascular risk factor. - **Mutation Distribution**: JAK2-mutated patients were older (median 62 years), while CALR-mutated and TN patients were younger (median 53 years). Female gender was more common in TN and JAK2-mutated cases. - **Thrombotic Events**: 19% had major thromboses at or prior to diagnosis, with arterial events (13%) outnumbering venous events (6%). The incidence of arterial events was higher than venous events. - **Prognostic Factors**: Older age (≥60 years), JAK2 mutation, and cardiovascular risk factors were significant risk factors for arterial thrombosis-free survival. JAK2 mutation was also a significant risk factor for venous thrombosis-free survival. - **Survival**: Overall survival was 27.1 years, with 10-year, 20-year, and 30-year survival rates of 86%, 64%, and 43%, respectively. Older age, male gender, absolute neutrophil count (ANC) ≥ 8 × 10^9/L, and absolute lymphocyte count (ALC) < 1.7 × 10^9/L were independent predictors of survival. - **Disease Progression**: 7% progressed to post-ET myelofibrosis (MF), with CALR and MPL mutations being significant risk factors. 2% progressed to blast phase, with older age and ANC ≥ 8 × 10^9/L being significant risk factors. The study highlights the importance of cytoreductive therapy and aspirin in mitigating thrombotic events and provides valuable insights into the natural history and prognosis of ET.This study presents a comprehensive analysis of 1000 patients with essential thrombocythemia (ET) seen at the Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM) in Florence, Italy, between 1980 and 2023. The median age of the patients was 59 years, with a higher proportion of females (65%). The most common mutations were JAK2 (66%), CALR (19%), and MPL (4%), with 11% being triple-negative (TN). Key findings include: - **Clinical and Laboratory Features**: 16% had extreme thrombocytosis (platelets ≥1000 × 10^9/L), 16% had leukocytosis (leukocytes >11 × 10^9/L), and 52% had at least one cardiovascular risk factor. - **Mutation Distribution**: JAK2-mutated patients were older (median 62 years), while CALR-mutated and TN patients were younger (median 53 years). Female gender was more common in TN and JAK2-mutated cases. - **Thrombotic Events**: 19% had major thromboses at or prior to diagnosis, with arterial events (13%) outnumbering venous events (6%). The incidence of arterial events was higher than venous events. - **Prognostic Factors**: Older age (≥60 years), JAK2 mutation, and cardiovascular risk factors were significant risk factors for arterial thrombosis-free survival. JAK2 mutation was also a significant risk factor for venous thrombosis-free survival. - **Survival**: Overall survival was 27.1 years, with 10-year, 20-year, and 30-year survival rates of 86%, 64%, and 43%, respectively. Older age, male gender, absolute neutrophil count (ANC) ≥ 8 × 10^9/L, and absolute lymphocyte count (ALC) < 1.7 × 10^9/L were independent predictors of survival. - **Disease Progression**: 7% progressed to post-ET myelofibrosis (MF), with CALR and MPL mutations being significant risk factors. 2% progressed to blast phase, with older age and ANC ≥ 8 × 10^9/L being significant risk factors. The study highlights the importance of cytoreductive therapy and aspirin in mitigating thrombotic events and provides valuable insights into the natural history and prognosis of ET.