Hydroxyurea (hydroxycarbamide, HU) is currently the only FDA-approved disease-modifying agent for individuals with sickle cell disease. Despite its efficacy in multicentered, randomized, placebo-controlled studies, HU remains highly underutilized among the sickle cell population. Several barriers to the use of HU have been identified including the need for frequent laboratory monitoring and physician visits. This study aimed to better assess the stability of patients' hematologic parameters when compliant with HU therapy to better determine the necessity of frequent routine laboratory monitoring. We conducted a retrospective review of 20 patients taking HU with record of good compliance. The within-subject coefficient of variation was computed as a measure of subject variability to better assess the stability of individual patients' blood counts to evaluate potential hematologic toxicity in subjects taking HU. Results demonstrated that during routine laboratory appointments, individuals' variability was very consistent; therefore assessment of significant change may be more accurately detected by individual symptomatology. Decreasing the stringency of the requirements for routine laboratory monitoring for patients on HU is unlikely to cause physicians to miss critical nadirs in absolute neutrophil count (or other laboratory values) and may lead to improved acceptance and use of this disease-modifying therapy in sickle cell disease.