Background: Venetoclax in combination with hypomethylating agents (HMAs) has become standard management for newly diagnosed older and unfit acute myeloid leukemia (AML) patients and an option for relapsed/refractory disease in cases unfit for aggressive therapy. Although venetoclax can lead to rapid tumor lysis syndrome (TLS) in chronic lymphocytic leukemia and therefore administrated in a weekly dose ramp-up to minimize toxicity, a modified dose ramp-up of venetoclax over 3–4 days in combination with HMAs has been investigated in AML trials without any reported cases of TLS (DiNardo et al, 2019). Notably, this trial prohibited azole fungal prophylaxis because of the known potentiation of venetoclax activity in that setting. Rare cases have been reported for venetoclax induced TLS in the context of CYP3A inhibition. This study presents cases with AML who developed TLS whilst receiving azacitidine/venetoclax combination. Notably, they shared similar pattern of disease progression. Methods: All AML patients who are unfit to receive induction chemotherapy, treated with venetoclax combination either upfront or in the salvage setting starting January 2019 until November 2019 were reviewed retrospectively. TLS was reported using Cairo-Bishop criteria (Cairo & Bishop, 2004), AML risk stratification and response evaluation by ELN-Leukemia NET. Results: We report fourteen cases treated with azacitidine/venetoclax combination, three cases developed venetoclax induced TLS despite following the TLS protocol per the phase 1b trial (administering allopurinol > 72 hours prior to initiation of venetoclax). All cases had intermediate to poor risk AML; all had WBCs < 25 k before starting venetoclax, 2 of 3 patients received CYP3A inhibitors for fungal prophylaxis. Disease burden, defined as per-cent of bone marrow involvement and peripheral circulating blasts, did not increase the risk of TLS. We observed TLS in newly diagnosed (n = 1) and in relapsed AML (n = 2). Also, with first initiation of venetoclax as well as with delayed onset and more prominent with azole fungal prophylaxis. All the cases of venetoclax induced TLS we observed, proved to be refractory to venetoclax combination after resumption of therapy. Conclusions: Venetoclax induced TLS is reportedly rare in AML. In our experience, TLS is more common in real world experience than has been previously reported. More prominent with azole fungal prophylaxis. Additionally, it appears to be associated with disease that proved ultimately refractory to venetoclax combination.