BACKGROUND Certain health conditions have been proven to have an effect on the severity of COVID-19, the disease caused by SAR-COV-2. The list of identified comorbid conditions includes hematological diseases, with sickle cell disease (SCD) falling into this category. CASE REPORT This case series examines the history, presentation, and clinical course of 5 patients with SCD who tested positive for SAR-COV-2 during the spring and summer of 2020. These patients experienced COVID-19 severities ranging from a mild cough and congestion to 8-day hospitalizations requiring blood transfusions. CONCLUSIONS While there is still a great amount of research on the interaction between COVID-19 and SCD needed, from this study we have concluded that patients with SCD do not always present with the classic COVID-19 triad of cough, shortness of breath, and fever. Often, these patients present with symptoms of vaso-occlusive crisis (VOC), including severe leg, flank, and chest pain, as was seen in 4 of 5 of our patients. We, and several other researchers, believe that this association between COVID-19 and VOC could be due to COVID-19 triggering inflammatory cytokines (notably IL-6) leading to system-wide inflammation, which induces sickling of the red blood cells. Based on this report, we recommend that SCD patients presenting with VOC who have had exposure to SAR-COV-2 be promptly tested for SAR-COV-2 to guide treatment and reduce mortality and morbidity in this vulnerable population.