Sickle cell disease (SCD) induces a chronic prothrombotic state. Central venous access devices (CVADs) are commonly used for chronic transfusions and iron chelation in this population. CVADs are an additional venous thromboembolism (VTE) risk factor. The role of thromboprophylaxis in this setting is uncertain. The objectives are: (1) to determine whether thromboprophylaxis reduces VTE risk in SCD patients with CVAD and (2) to explore characteristics associated with VTE risk. We identified adults with SCD and CVAD intended for chronic use (≥3 months) at two comprehensive SCD centers. Thromboprophylaxis presence; type; intensity; and patient-, catheter-, and treatment-related VTE risk factors were recorded. Among 949 patients, 49 had a CVAD (25 without and 24 with VTE prophylaxis). Thromboprophylaxis type and intensity varied widely. Patients without thromboprophylaxis had higher VTE rates (rate ratio (RR) = 4.0 (95% confidence interval: 1.2–12.6), p = 0.02). Hydroxyurea was associated with lower VTE rates (RR = 20.5 (6.4–65.3), p < 0.001). PICC lines and Vortex and Xcela Power implantable devices were associated with higher rates compared with Port-a-Cath (RR = 5.8 (1.3–25.9), p = 0.02, and RR = 58.2 (15.0–225.0), p < 0.001, respectively). Thromboprophylaxis, hydroxyurea, and CVAD subtype were independently associated with VTE. The potentially protective role of thromboprophylaxis and hydroxyurea for VTE prevention in patients with SCD and CVAD merits further exploration.