The COVID-19 pandemic disproportionately affected persons with underlying medical conditions. SARS-CoV-2 infection susceptibility and vaccine effectiveness in pediatric hematology-oncology patients were unknown. From February to July 2022, anti-spike and anti-nucleocapsid Ig were assayed in 354 pediatric hematology-oncology subjects, including 53 oncology patients receiving chemotherapy (cancer), 150 patients with sickle cell disease (SCD), and 151 benign consult and long-term follow-up patients (controls). Participants completed a questionnaire. Frequencies of COVID-19 infection, defined by positive PCR/antigen test or anti-nucleocapsid Ig, were 62% in cancer, 71% in SCD, 52% in controls, with SCD statistically different than controls (p=.001). Infection was associated with COVID-19 exposure, Hispanic/Latino or Black/African American ethnicity, multi-family dwelling, sports participation; COVID-19 booster decreased association with infection. In COVID-19-positive cancer patients, 58% had positive anti-nucleocapsid and 76% had positive anti-spike (≥10U/mL), compared to essentially 100% seroconversion in SCD and controls (p<.0001, p=.01, respectively). Infection led to high anti-spike (≥2500U/mL) in 12% cancer, 14% SCD, and 15% controls (p=.93). Vaccination resulted in anti-spike positivity in 90% cancer, 100% SCD, and 100% controls (p=.06), and in high anti-spike in 20% cancer, 47% SCD, and 41% controls (p=.36). Of boosted subjects, one of two cancer, 6/6 SCD, and 19/19 controls exhibited high anti-spike. Cancer patients demonstrated similar SARS-CoV-2 infection frequency as controls, but diminished antibody response to infection and vaccination. SCD patients exhibited seroconversion indistinguishable from controls. Vaccination was associated with higher frequency of high anti-spike than infection; vaccination plus booster was most effective in eliciting high anti-spike antibody detectable beyond 90days.