Previous reports about the Creteil newborn-cohort (1988/Apr-2007) showed that the risk of silent cerebral infarcts (SCI) remained high (37.1%) by age 14 in children with sickle cell anemia (SCA) and intracranial time-averaged mean maximum velocity (TAMMV)≥200cm/s despite chronictransfusion. Systematic assessment of extracranial internal carotid artery (eICA) since June-2011 revealed that SCI-risk is associated with chronic or acute anemia and eICA-stenosis. Based on these results, SCA-children with eICA-TAMMV≥200cm/s or eICA-stenosis were placed on chronictransfusion and considered for allogeneic stem-cell transplantation (alloSCT). SCA-children with 160-199cm/s eICA-TAMMV were maintained on hydroxyurea. We hypothesized that detection/management of eICA-arteriopathy and wider use of hydroxyurea could reduce SCI-incidence. Comparison between the new cohort (May-2007/Dec-2014) eICA-assessed before age 4 with wider but not systematic use of hydroxyurea and the earlier cohort (1988/Apr-2007) never eICAassessed until the 2008 update, revealed a significant reduction of SCI-risk (Log-Rank, P=.009) associated with eICA-assessment but not with wider use of hydroxyurea. eICA-TAMMVs≥160cm/s, even with no eICA-stenosis, were risk-factors for SCI, suggesting that all SCA-children with eICATAMMV≥ 160cm/s should be placed on chronic-transfusion. Hydroxyurea initiation at an early age was associated with lower intracranial-arteriopathy incidence, but not with lower eICA-arteriopathy and SCI-incidence. In the overall cohort (1988-2014), including 332 SCA-children, all assessed/managed for eICA-arteriopathy after 2011, the cumulative-SCI-incidence by age 14 was 25.0% (95%CI:19.0%-31.0%). SCI-risk was associated with being older at first-neck-MRA and having high MCV on hydroxyurea. While the impact of hydroxyurea on SCI-incidence remains unclear, making controlled trials necessary, eICA-arteriopathy management by intensive therapy is effective at improving SCIprevention.