OBJECTIVES: The aim of this study was to characterize the clinical features and outcomes of patients with JAK2 V617F- and CALR-unmutated essential thrombocythemia (ET) and to identify potential driver mutations through whole-exome sequencing (WES). METHODS: This was a cross-sectional study including patients diagnosed with ET between 2007 and 2024. Clinical characteristics and outcomes were compared between patients with and without JAK2V617F and CALR mutations. WES was analyzed in JAK2V617F- and CALR-unmutated ET patients. RESULTS: Thirty-nine out of 162 ET patients (24%) were JAK2V617F- and CALR-unmutated. This group was younger than patients in the JAK2V617F mutated group (mean age 53.7 vs. 61.1 years, p = 0.012) and had lower incidence of thrombotic events (5.1% vs. 9.1%, p = 0.327). The median overall survival was 13.51 years compared to 12.61 years in patients with JAK2V617F or CALR mutations (p = 0.63). There were no statistically significant differences in clinical symptoms, incidence of thrombosis, bleeding, myelofibrosis, or leukemic transformation. WES was analyzed in 15 patients. Uncommon MPL mutations were identified, including MPLL265F, MPLP70L, and MPLR321Q. Potential novel CALR mutations were detected in exon 5 (c.540C > T, N180 = ) and exon 6 (c.703-3del). Non-driver gene mutations were detected, including RUNX1 (57.1%), ASXL1, DNMT3A, SETBP1, and MSH6. DISCUSSION AND CONCLUSIONS: Patients with JAK2V617F- and CALR-unmutated ET tend to present at a younger age and exhibit a lower incidence of thrombosis compared to those with JAK2V617F-mutated ET. The application of WES enabled the detection of uncommon and potential driver mutations in JAK2V617F- and CALR-unmutated ET.