This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Three clusters were identified. Cluster 1 (n = 123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n = 102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n = 154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n = 33) included the majority of pre-capillary PH whilst cluster 2 (n = 34) included post-capillary PH. No PH was found in cluster 3 (n = 27). After a follow-up of 11.4 ± 2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate versus 12% in cluster 1 and 5% in cluster 3 (p log-rank = 0.003). Cluster analysis of echocardiography variables identified three hemodynamic and clinical phenotypes among SCD patients, each predicting a different prognosis.