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Based on a prospective cohort study of 1056 patients with sickle cell anemia (Hb SS) initiated in 1959, we investigated the influence of calendar era, age, sex, and prior medical conditions on the subsequent development of irreversible organ damage and survival using the Cox regression model with time-dependent covariates adjusting for all prior occurrences. We studied 30 acute clinical events, and focused on 8 prototypic forms of irreversible organ damage. Childhood survival to age 20 years has improved from 79% for those born before 1975 to 89% for children born in or after 1975. Bone infarction was a significant risk factor for avascular necrosis (p = 0.01), and infantile dactylitis was a significant risk factor for stroke (p = 0.01). Prior hospitalized vaso-occlusive sickle crisis in adults was significantly associated with the increased rate of avascular necrosis (p < 0.001), leg ulcers (p < 0.001), sickle chronic lung disease (p < 0.001), renal failure (p < 0.005), and early death (p < 0.001). The diagnosis of clearly evident clinical conditions such as leg ulcer, osteonecrosis, and retinopathy predicted an increased likelihood of developing a more lethal form of organ damage and earlier death: 77% of patients with chronic lung disease, 75% of those with renal insufficiency, and 51% of those with stroke had a prior chronic condition. Of the 232 patients who died, 73% had 1 or more clinically recognized forms of irreversible organ damage. By the fifth decade, nearly one-half of the surviving patients (48%) had documented irreversible organ damage. End-stage renal disease (glomerulosclerosis), chronic pulmonary disease with pulmonary hypertension, retinopathy, and cerebral microinfarctions are manifestations of arterial and capillary microcirculation obstructive vasculopathy. The current study underscores the need for preventive therapy to ameliorate the progression of the sickle vasculopathy.