Background: Persistence of minimal residual disease (MRD) post therapy is a powerful predictor of outcome in patients with AML treated with traditional cytarabine and anthracycline based regimens. The clinical relevance of MRD in the context of hypomethylating agents has not been evaluated extensively. Methods: Among 194 patients with AML treated with single agent azacytidine, decitabine, or gaudecitabine, 116 (median age 76, range 60 - 92) had MRD analysis performed on bone marrow specimens obtained at time of assessment of response or thereafter; among them 69 (59%) achieved either morphologic complete remission (CR) or CR with incomplete recovery of platelets (CRp) or counts (CRi), and 61 (53%) had evaluable MRD data; MRD was assessed using an 8-color flow panel, with a detection sensitivity of 0.01%. Results: Median cycles to achieving response was 2 (range, 1-6). Sixty one patients had evaluable MRD data at the time of response, of whom 19 (28%) became MRD negative (-). This was associated with a reduced cumulative risk of relapse (p = 0.012) but did not translate to an improved relapse-free survival (RFS; p = 0.17) or overall survival (OS; p = 0.79) due to high frequency of non-relapse deaths (attributable to comorbidities and infections) in the MRD- group. Patients who achieved a MRD- state at the time of achieving response had a higher mortality [5/8 (62%)] when compared with those who achieved a MRD- state in subsequent cycles [1/13 (7.6%); p = 0.01], resulting in an inferior OS (6.2 months (mo) vs 20 mo, p = 0.012). Similarly, achieving negative MRD at CR and at any time up to 3 months post response was not associated with improved RFS or OS despite a lower cumulative risk of relapse (p = 0.045). There was no impact of MRD, on OS, whether the MRD- state was achieved after 1^st, 3^rd or 6^thcycle of therapy. Association between depth of MRD response at time of remission and RFS was borderline significant (p = 0.08). On multivariate analysis, response (CR vs CRi/CRp), but not a negative MRD, was predictive for RFS or OS. Conclusions: In this cohort of older AML patients treated with hypomethylating agents, achieving a MRD- state was associated with a reduced risk of relapse but not improved RFS or OS.