IntroductionInfections may play a role in the etiology of childhood cancer and immunizations may be protective because vaccinations stimulate the immune system. Observational studies reported inconsistent associations between vaccination and risk of childhood cancer. Since a synthesis of the evidence is lacking, we conducted a meta-analysis stratified by histological and site-specific cancer.MethodsWe performed a systematic review (CRD42020148579) following PRISMA guidelines and searched for literature in MEDLINE, Embase, and the Science Citation Index databases. We identified in three literature databases 7,594 different articles of which 35 met the inclusion criteria allowing for 27 analyses of 11 cancer outcomes after exposure to nine different types of vaccinations. We calculated summary odds ratios (ORs) and 95% confidence intervals (CIs) using random effects models.ResultsWe observed four inverse associations between childhood leukemia and certain vaccines as well as the number of vaccinations: OR 0.49 (95% CI = 0.32 to 0.74) for leukemia death after bacillus Calmette–Guérin vaccination; OR 0.76 (95% CI = 0.65 to 0.90) for acute lymphoblastic leukemia after Haemophilus influenzae type b vaccination; OR 0.57 (95% CI = 0.36 to 0.88) for leukemia; and OR 0.62 (95% CI = 0.46 to 0.85) for acute lymphoblastic leukemia after three or more vaccinations of any type. All other conducted analyses did not show any associations.DiscussionThe results are consistent with the hypothesis that vaccinations reduce the risk of childhood leukemia. However, the robustness and validity of these results is limited due to the small number, substantial heterogeneity, and methodological limitations of available studies.