Background Sickle Cell Disease is a cause of anemia frequently requiring blood transfusions. Current treatments for Sickle Cell Anemia include Hydroxyurea, or the recently approved medication in 2019, Voxelotor. Although recent research, such as the HOPE study, has shown that Voxelotor increases hemoglobin levels when compared to Hydroxyurea, there is limited data regarding the requirement of blood transfusions in patients with Sickle Cell Disease when comparing the two medications. We conducted a retrospective cohort study to determine the requirement of blood transfusions in hospitalized patients with Sickle Cell Disease who were on either taking Voxelotor or Hydroxyurea. Methods This retrospective cohort study identified 8,815 patients across several facilities diagnosed with Sickle Cell Disease who were taking outpatient Voxelotor or Hydroxyurea. Patients who had CKD Stage 4 or 5, ESRD, pregnancy, major surgery, normal hemoglobin levels, and elevated liver enzymes were excluded with a final sample of 6,240. Patients were stratified into two groups based on the treatment they were on, a group taking Voxelotor (243 patients 3.92%) and a group taking Hydroxyurea (5961 96.08%) outpatient. We assessed patient's characteristics such as age, sex, race, smoking status and events during hospitalization. The primary outcome was the number of blood transfusions required with either treatment. Zero-inflated Poisson regression was used to determine the quantity and prediction of blood transfusions required according to different characteristics. Results Of the 6,240 with Sickle Cell Disease who were either on Voxelotor or Hydroxyurea the mean age was 31.32 years, 58.11% were female and 41.89% were male, 94.63% were African-American and 5.37% were non-African-Americans. The medication group was not significantly associated with the log count of transfusions (ie. increased number of transfusions), when controlling for other variables (χ 2 = 0.81, p = 0.367). The odds ratio is 0.425, indicating that patients on Voxelotor are 0.4247 times as likely to be in the “certain zero” group as those on Hydroxyurea - in other words, patients taking Hydroxyurea are 2.354 (1/0.425) times as likely to be in the “certain zero” group (i.e., patients on Hydroxyurea are 2.354 times as likely to not need a transfusion compared to patients taking Voxelotor). Conclusion Hospitalized patients with Sickle Cell Disease taking Voxelotor or Hydroxyurea outpatient have similar blood transfusions requirements when controlling for other variables. In the case of Voxelotor, it is known to increase hemoglobin levels more than Hydroxyurea in patients with Sickle Cell Disease, but there is limited data regarding the end requirements of blood transfusions when comparing the two medications. Our study is the first to identify that there was no increased requirement in the quantity of blood transfusions (Wald Chi Square 26.36, p<.0001, CI 0.3063~ 0.5890) when comparing each medication group. However, the limitation is having a relatively small sample size, and possible confounders from the patients and the disease itself. Further research is required to investigate this.