Sickle cell disease (SCD) is associated with extensive morbidity and early mortality. Although the most common known causes of death for adults with SCD are acute chest syndrome, stroke, pulmonary hypertension, and infection, the direct cause of death is frequently undefined, and patients often die suddenly. In one series of 306 autopsies of patients with SCD, death was sudden and unexpected in 41% of cases (Manci et al 2003). The incidence of sudden cardiac death and associated risk factors in patients with SCD are currently unknown. We sought to identify risk factors for mortality in adult subjects with SCD and to evaluate the frequency, risk factors and co-morbidities of sudden death in this population. We identified 43 adult patients (21 males and 22 females) who had been followed in the SCD clinic at Duke University Medical Center (DUMC) and who had died between January 2000 and April 2005. Clinical characteristics and laboratory data were evaluated by retrospective chart review. Findings were compared with data from patients who were actively followed during the same time period and were still living (n=197). The average age at death was 44.3 years (range 21–83). The most frequently listed causes of death were liver failure, multiorgan failure, stroke, and pulseless electrical activity (PEA) arrest. The etiology of death in 29 of the 43 patients was unknown. Recognized risk factors for sudden cardiac death, including ejection fraction (52% vs. 54%), left ventricular size (LVIDd 5.0cm vs. 5.2cm), and fractional shortening (0.30 ±0.01 vs. 0.33± 0.01) as measured by echocardiogram, were not significantly different between deceased and living patients, respectively. Left ventricular hypertrophy (LVH), defined as a left ventricular mass index ≥134 and ≥110 g/m2 for men and women, was reported in 41% of the deceased patients but in only 31% of living subjects. Of the 12 deceased patients with LVH, 7 had mild LVH and 5 had moderate-severe LVH. The average tricuspid regurgitant jet velocity measured by Doppler echocardiogram was higher in patients who died compared to those who were still living (3.72 vs. 2.17 m/s). The most frequently documented cardiopulmonary complications among deceased patients were acute chest syndrome/pneumonia, pulmonary hypertension, systemic hypertension, and stroke. Identified risk factors associated with premature death were pulmonary hypertension (p<0.0001) and severe anemia (p=0.002). Baseline WBC count and oxygen saturation were not significantly different between deceased and living patients. We conclude that despite improved medical care and therapeutic advances, adult patients with SCD continue to experience a high rate of premature mortality, and a significant number of patients die suddenly. The etiology of death is frequently multifactorial and poorly defined. Identifying the variables contributing to sudden death in SCD patients may enable clinicians to successfully intervene and prevent early demise.