The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥1x10-4 were enrolled in this phase II trial. Inotuzumab was administered at 0.6 mg/m2 on Day 1 and 0.3 mg/m2 on Day 8 of cycle 1, then at 0.3 mg/m2 on Days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome-positive ALL. Fifteen (58%) had baseline MRD ≥1x10-3. A median of three cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival (RFS) rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in two (8%) patients. In summary, inotuzumab ozogamicin resulted in favorable survival, MRD-negativity rates, and safety profile in patients with ALL and MRD-positive status. This study is registered at ClinicalTrials.gov (NCT03441061).