HyperCVAD is a commonly-used regimen for adults with newly-diagnosed acute lymphoblastic leukemia (ALL). However, relatively little is known about the application of minimal residual disease (MRD) detection with this treatment. To address this, we studied 142 adults with ALL treated with hyperCVAD over a 10-year period who had MRD assessed by either multi-parameter flow cytometry or (for patients with Philadelphia chromosome positive ALL) reverse transcriptase polymerase chain reaction for the BCR-ABL1 translocation. In a multivariate analysis, patients who achieved MRD negativity (MRD ) at any point had significantly better overall survival (OS; hazard ratio [HR] 0.43; P = .01) and event-free survival (EFS; HR 0.27; P < .01). Of 121 patients with MRD assessed at various points within 90 days of starting hyperCVAD, 50% (n = 61) had achieved MRD . Among those that became MRD , the median time to MRD was 68 days. Time to MRD was significantly associated with EFS (P = .009), but not OS (P = .19), implying increasingly better EFS the earlier MRD is achieved. These data add to our understanding of MRD assessment during treatment with hyperCVAD, aide clinicians with predicting relapse risk, and provide additional historical data on which future clinical trials can be designed.