Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignancies has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104,062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first three years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for three months prior to conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring over one year of age (adjusted relative risk: 7.99 [95% confidence interval: 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring over one year of age. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignancies.