The European LeukemiaNet recently proposed specific Clinical Signs and Symptoms (CSSs) that may trigger cytoreduction in patients with polycythemia vera (PV) at low thrombotic risk (LR). To evaluate the impact of CSSs on the thrombotic risk of patients at LR, high risk by age only (HR-AGE) or by previous thrombosis (HR-THRO), we conducted a multicenter cooperative study (NCT06134102) involving 739 PV patients treated with first-line hydroxyurea. At hydroxyurea start, 443 patients had at least one CSS. In patients with and without CSSs, the incidence rate ratio of thrombosis was 2.2 and 0.7 per 100 patient-years, respectively (p < 0.001), and the thrombosis-free survival (TFS) adjusted for delayed entry at 5 years was 88.7% and 96.1% (p < 0.001). The best 5-years TFS was observed in LR and HR-AGE with no CSSs (LR, 100%; HR-AGE: 98.1%). LR, HR-AGE patients with CSSs and HR-THRO patients without CSSs had comparable TFS (89.2%, 92.1% and 88.8%, respectively). TFS of HR-THRO patients was 80.2%. In multivariate analysis including each CSS, inadequate hematocrit control (HR: 2.32, p < 0.001), relevant CVRFs (HR: 2.87, p = 0.006), progressive splenomegaly (HR: 4.02, p = 0.03) and previous thrombosis (HR: 3.76, p < 0.001) remained significantly associated with thrombotic risk. CSSs identify an increased thrombotic risk phenotype across all risk categories.