Background: V enetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more robust data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. Procedure: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco (UCSF) Benioff Children’s Hospitals from 2016 to 2022. Results: We identified 13 patients (AML , n= 8, B-ALL, n= 3, MDS, n= 2) aged 4 months to 27 years. A median of 3 prior lines of therapy were given (range 0 to 5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved a complete remission (CR); 2 (15%) achieved a partial remission (PR); 3 (23%) had stable disease (SD), and 5 (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5 to 52 months), and 3 months (range 2 weeks to 7.5 months), respectively. Five patients (38%) developed life-threatening infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, encephalitis with bacterial brain abscesses. Conclusions: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but was frequently associated with severe atypical infections, particularly in combination with cytotoxic chemotherapy.