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Background Children develop symptomatic coronavirus disease 2019 (COVID-19) more rarely than adults upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pediatric oncology and hematology patients may be at increased risk of severe COVID-19 due to their underlying disease or treatment. We investigated COVID-19 and seroprevalence of anti-SARS-CoV-2 antibodies, respectively, in a Swedish cohort of pediatric oncology and hematology patients. Procedure Patients (n = 136) were recruited between June 2020 and September 2021 at Uppsala University Children's Hospital, Sweden. Up to six consecutive blood samples per patient were analyzed for wild-type anti-S1 IgM and IgG antibodies (including after vaccination, n = 4). Clinical data on COVID-19 (including polymerase chain reaction [PCR] test results) were collected from electronic medical records. A questionnaire was completed at recruitment. Results A cumulative seroprevalence (IgM and IgG) of 33% (45/136 patients, 95% confidence interval: 25%–41%) was observed in this patient cohort, of whom 66% (90/136 patients) were under severe immunosuppressive treatment during the study period. Increasing patient age (p = .037) and PCR test results (p < .002) were associated with seropositivity in nonvaccinated cases. Most seropositive, nonvaccinated cases (32/43, 74%) were never PCR-verified for SARS-CoV-2 infection. Of the 13 patients with PCR-verified infection, nine (69%) reported mild disease. A majority (63%) reported continued school attendance during the pandemic. Conclusions Swedish pediatric oncology and hematology patients developed antibodies against SARS-CoV-2, despite their diagnosis and/or treatment, and the observed seroprevalence was similar to that in national pediatric outpatients. PCR-verified cases underestimate the true incidence of COVID-19 in this patient cohort.