Altered mitochondrial function occurs in sickle cell disease (SCD), due in part to low nitric oxide (NO) bioavailability. Arginine, the substrate for NO production, becomes acutely deficient in SCD patients with vaso-occlusive-painful-events (VOE). To determine if arginine improves mitochondrial function, 12 children with SCD hospitalized for VOE (age 13.6±3 years, 67% male, 75% HbSS) were randomized to one of three arginine doses: 1) 100mg/kg IV three times/day (TID,n=4); 2) Loading dose (200mg/kg) then 100mg/kg TID (n=4); or 3) Loading dose (200mg/kg) followed by continuous infusion (300mg/kg/day) until discharge (n=4). Platelet-rich-plasma mitochondrial activity, protein expression, and protein-carbonyls were measured from ED-presentation vs. discharge. All VOE subjects at ED-presentation had significantly decreased complex-V activity compared to a steady-state cohort. Notably, complex-V activity was increased at discharge in subjects from all 3 arginine-dosing schemes; greatest increase occurred when utilizing a loading dose (p<0.001). While complex-IV and citrate synthase activities were similar in VOE platelets vs. steady state, enzyme activities were significantly increased in VOE subjects after arginine-loading dose treatment. Arginine therapy also decreased protein-carbonyl levels across all treatment doses (p<0.01), suggesting a decrease in oxidative stress. These data suggest that arginine therapy increases mitochondrial activity and reduces oxidative stress in children with SCD/VOE.