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Objectives and methods: We conducted a retrospective analysis to evaluate the outcomes of 28 heavily pretreated (median 3 (2‐6) treatment lines, sixteen (57%) allotransplanted) relapsed/refractory acute myeloid leukemia patients who had failed salvage venetoclax‐based therapies. Results: The median age was 59 years (20‐80), 20 patients (71%) had ECOG 2‐4 status, and 18 patients (64%) were stratified to European Leukemia Network 2017 adverse risk group. The most common mutations were ASXL1 (21%), RUNX1 (18%), FLT3 ITD/TKD (18%), PTPN11 (15%), NRAS/KRAS (15%), and WT1 (15%). Twenty‐two patients (79%) received different post‐venetoclax salvage therapies with the overall response rate of 23% (complete remission + morphological leukemia‐free state). Three of six (50%) patients achieved complete remissions after therapy with venetoclax + actinomycin D ± low‐dose cytarabine. The remaining 6 patients did not receive any further salvage treatment mainly due to poor general condition. The median overall survival was 3.9 months for all patients (4.3 for those receiving post‐venetoclax salvage vs 1.3 months receiving palliative care alone, P <.001). Conclusions: Though the remission rate and survival of patients failing venetoclax are poor, a small proportion of these R/R AML patients may still respond to cautious intensification of chemotherapy with venetoclax. [ABSTRACT FROM AUTHOR]