PURPOSE: Acetaminophen ( METHODS: This retrospective, multi-center analysis extracted APAP prescribing data from the Pediatric Health Information System® ( FINDINGS: PHIS records for the complete years of 2004-2021 yielded 388,364 inpatient encounters for 50,779 unique patients. Of these, 87.3% of patients received APAP. Although APAP-opioid combination use was infrequent overall, children receiving APAP were more likely to receive an APAP-opioid combination medication (N=25,880, 13.4%, p <
0.002) compared to those who did not receive APAP. Among specialty children's hospitals, national APAP use was stable over the study period. Regionally, APAP use increased among hospitals in the Northeast. APAP-opioid combination use decreased nationally with regional variation. In contrast to the steady decline in other regions, Southern APAP-opioid combination use was consistently elevated before declining in 2014. IMPLICATIONS: This article describes acetaminophen and acetaminophen-opioid prescribing trends among children with cancer in the United States. These trends are key to help clinicians assess changes in pain management strategies over time, contextualize analgesic exposure and efficacy, and provide a foundation for future studies in drug safety. Extensive acetaminophen use can affect liver health, and further work is needed to evaluate acetaminophen exposure in children with cancer. DATA STATEMENT: Deidentified data were obtained and evaluated under an IRB-approved protocol. Due to privacy requirements, the data are not available to be shared.