Background: Internal jugular vein thrombosis (IJVT) is a rare but serious complication in hospitalized patients, often associated with central venous access devices (CVADs). The primary objective of the study was to analyze the clinical characteristics of patients with newly diagnosed IJVT, in particular to evaluate mortality, development of pulmonary embolism and incidence of bleeding at 30 days from diagnosis. Secondly, a sub-analysis was performed between patients with device-related and non-device-related thrombosis. Methods: Prospective study on adult inpatients diagnosed with IJVT from January to December 2024. Data on demographics, comorbidities, device use, laboratory values at diagnosis (D-dimer, platelet count, C-reactive protein (CRP), liver/renal function), treatment, and outcomes (mortality, pulmonary embolism, bleeding) were collected. Results: Thirty-one patients with IJVT were included. Mean age was 71.0 ± 13.2 years; 54.8% female; 35.5% had CVADs (central venous catheter (CVC) 36.4%, midlines 36.4%, peripherally inserted central catheter (PICC) 27.2%). Device-associated IJVT patients exhibited lower D-dimer (2.1 ± 0.5 vs. 3.6 ± 0.8 µg/mL; p = 0.018), higher platelet counts (249.0 ± 86.7 vs. 184.3 ± 53.6 × 10⁹/L; p = 0.044), and elevated CRP (12.5 ± 9.2 vs. 5.1 ± 5.6 mg/L; p = 0.033). Overall mortality was 16.1%; pulmonary embolism occurred in 16.1% and bleeding in 6.5%. CVAD use was not independently associated with adverse outcomes. Conclusions: IJVT presents with distinct biomarker profiles when associated with CVADs, characterized by lower systemic fibrinolysis and heightened inflammation. Recognition of these differences may refine diagnostic thresholds and guide prophylactic strategies. Larger prospective studies are warranted.