Background: Although echocardiography-derived tricuspid regurgitant jet velocity (TRV) is associated with increased mortality in sickle-cell disease (SCD), it is unclear whether increased TRV is a marker of multiorgan disease due to systemic vasculopathy or related to increased pulmonary artery systolic pressure with episodes of multiple acute chest syndrome (ACS). Methods: Our study analyzed 148 consecutive patients with transthoracic echocardiography with TRV data, who came to our adult SCD Clinic at the Wake Forest Baptist Medical Center. For our analysis, we took TRV ≥2.5 m/s as elevated. Patients were followed on average for 9 years. Results: TRV ≥3 m/s was significantly associated with increased mortality (p < 0.001), thromboembolism (p < 0.001), hospitalization for ACS (p < 0.001), supraventricular arrhythmia (p = 0.028), right ventricular (RV) dilation, decreased hemoglobin and increased creatinine. Patients with a progressive increase in TRV during follow-up had increased mortality (36.7 vs. 8.6%, p = 0.007) and increased ACS (45 vs. 5.7%, p < 0.001). Death was independently associated with TRV ≥3 m/s (p = 0.023), ACS (p = 0.001) and increased RV basal diameter (p = 0.003). Conclusions: TRV is an important global marker for the severity and progression of SCD, and carries a significant prognostic implication.