BACKGROUND Indisulam possesses anticancer properties through down‐regulation of various cell‐cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors. METHODS The authors designed a phase 2 study of indisulam in combination with idarubicin and cytarabine in patients who had relapsed/refractory acute myeloid leukemia AML and high‐risk myelodysplastic syndrome. In stage 1, patients received intravenous indisulam at 400 mg/m2 on days 1 and 8 of a 28‐day cycle. If they had no response, then patients received same dose schedule of indisulam followed by intravenous idarubicin 8 mg/m2 daily for 3 days and cytarabine 1.0 g/m2 over 24 hours daily on days 9 through 12 (for those aged < 60 years) or days 9 through 11 (for those aged > 60 years) of a 28‐day cycle. Primary endpoints included the overall response rate, and secondary objectives included overall survival. RESULTS Forty patients were enrolled. Of the 37 evaluable patients, 31 received indisulam with chemotherapy. Of these, 11 (35%) responded for a median duration of 5.3 months. The estimated 1‐year overall survival rate was 51% for responders compared with 8 % for nonresponders (P < .001). The most common grade ≥3 nonhematologic toxicities were electrolyte abnormalities (50%) and febrile neutropenia (28%). CONCLUSIONS The combination of indisulam with idarubicin and cytarabine yielded a 35% response rate in heavily pretreated patients with AML. With emerging data identifying the expression of DCAF15 (DDB1 and CUL4‐associated factor 15) as a potential biomarker for activity, the combination of indisulam with idarubicin and cytarabine should be studied in a biomarker‐driven trial or in patients who have splicing factor mutations. Cancer 2018;124:2758‐65. © 2018 American Cancer Society. Cancer 2018;124:2758‐2765. © 2018 American Cancer Society Indisulam is a cell‐cycle checkpoint inhibitor that produces in combination with cytarabine and idarubicin a 35% response rate in heavily pretreated patients with acute myeloid leukemia. This combination deserves evaluation in patients who have acute myeloid leukemia with splicing factor mutations, because the antineoplastic activity of indisulam depends on DCAF15 and RBM39.