Sickle Cell Disease is among the top 20 causes of mortality worldwide. Hydroxyurea is one of the most readily available and economical solutions approved for the treatment of Sickle Cell Disease patients: it induces the synthesis of foetal haemoglobin and decreases the inflammatory phenotype. Hydroxyurea shows high interindividual variability, re-quiring individualized dosing to balance therapeutic efficacy against escalating toxicity. In addition to non-genetic factors, hereditary variables can also be investigated to adopt a more tailored dosing regimen according to each patient's demographic, pharmacokinetic and pharmacogenetic profile. This study evaluated the possible influence of different genetic variants on hydroxyurea pharmacokinetics, by conducting a retrospective analysis on 79 treated patients, stratified by ethnicity, age and sex. SLC22A3*698 C>G variant was found to be the most significantly associated with an en-hanced function of the encoded transporter, improving the drug elimination process. ABCB1 1236 C>T, ABCB1 2677 G>A, ABCB1 3435 C>T, CYP2B6 516 G>T, CYP2C19*2 G>A, CYP2C9*3A A>C, CYP2D6*10 A>G, MAP3K5 13257 C>T, MAP3K5 6292 C>A and OCT1 480 C>G gene variants were instead found linked to a general loss-of-function phenotype, reflecting slower and less efficient drug metabolism. These findings demonstrate the importance of assessing hydroxyurea pharmacogenetics while taking into account different ethnic and demographic variables, in order to support a more personalized and effective therapeutic approach for sickle cell disease patients.