Benefits of serial electrocardiographic (ECG) monitoring to detect QT prolongation in patients with hematological malignancies remain unclear. This retrospective, single-center, study evaluated 316 adult acute leukemia and high-risk MDS patients who received 11,775 patient-days of voriconazole prophylaxis during induction chemotherapy. Of these, 37 patients (16.2%) experienced QTc prolongation. Medications associated with QTc prolongation included furosemide, haloperidol, metronidazole, mirtazapine, prochlorperazine, and venlafaxine. Hypokalemia and hypomagnesemia were also significantly associated with QTc prolongation (HR 3.15; p = .003 and HR 6.47, p = .007, respectively). Management modifications due to QTc prolongation included discontinuation of QT prolonging medications (n = 25), more aggressive electrolyte repletion (n = 5), and enhanced ECG monitoring (n = 3). One patient with multiple QT prolonging factors experienced possible Torsades de Pointes. Overall mortality was 15% with no cardiac-related deaths. Serial ECG monitoring during induction chemotherapy can be tailored proportionally to QT-prolonging risk factors. Management should include aggressive electrolyte repletion and avoidance of concurrent QT prolonging medications.