Blood cell membranes in sickle cell disease (SCD) have low docosahexaenoic acid (DHA). DHA treatment reduces sickle cell crisis (SCC) rate and ameliorates the inflammation, oxidative stress, and hypercoagulable state of SCD. SC411 is a novel DHA Et ester formulation with a proprietary delivery platform (Advanced Lipid Technol.) that enhances DHA bioavailability. The SCOT trial investigated the effect of 3 different doses of SC411 on clin. and biochem. endpoints in 67 children with SCD (5-17 years old). Seventy-six percent of subjects were also receiving hydroxyurea. After 4 wk of treatment with SC411 at 20, 36, and 60 mg DHA/kg per day or placebo a statistically significant (P < .001) mean percentage increase of blood cell membrane DHA and eicosapentaenoic acid was seen vs baseline: 109.0% (confidence interval [CI], 46.7-171.3), 163.8% (CI, 108.3-219.2), 170.8% (CI, 90.2-251.4), and 28.6% (CI, 250.1 to 107.3), resp. After 8 wk of treatment, statistically significant changes vs placebo were also observed in D-dimer (P = .025) and soluble E-selectin (P = .0219) in subjects exposed to 36 mg/kg. A significant increase in Hb was observed against placebo in subjects receiving 20mg DHA/kg per day (P = .039). SC411 significantly reduced electronic diary recorded SCC, analgesic use at home, and days absent from school because of sickle cell pain. The lower rate of clin. SCC observed in the pooled active groups vs placebo did not reach statistical significance (rate ratio, 0.47; 95% CI, 0.20-1.11; P = .07). All tested doses were safe and well tolerated.