Objective: This pilot study examined whether methylphenidate (MPH) was effective in enhancing cognitive performance and attention for children with sickle cell disease (SCD) with cerebrovascular complications who evidence attention problems. Methods: In this multisite, pilot study, we evaluated 2 separate double-blind controlled clinical trials, including a laboratory trial of the short-term efficacy of MPH, with the second study a 3-week home/school crossover trial evaluating the efficacy of MPH. The laboratory trial included 14 participants between the age of 7 and 16 years. Assessments included measures of sustained attention, reaction time, executive functions, and verbal memory. The home/school trial included 20 participants. The outcome measures were parent and teacher ratings of attention. The first study compared MPH with placebo, while the second trial compared placebo, low-dose (LD) MPH, and moderate-dose MPH. Results: In the laboratory trial, significant effects were revealed for measures of memory and inhibitory control. Parent and teacher reports from the home/school trial indicate that moderate-dose MPH produced superior improvement in attention relative to the placebo and LD MPH. Conclusions: Stimulant medication positively impacted select measures of memory and inhibitory control in some children with SCD. Attention, as rated by parent and teachers, was improved for a greater number of children and adolescents on higher doses of MPH relative to LD MPH and placebo. Stimulant medication may provide an effective intervention for some children with SCD and cerebrovascular complications who demonstrate attention problems.