Detection of minimal residual disease (MRD) to guide therapy has been standard practice in treatment of childhood acute lymphoblastic leukemia (ALL) for decades. In multiple myeloma (MM), a clear correlation is found between absence of MRD and longer survival. Quantitative allele-specific oligonucleotide (qASO)-PCR is the standard molecular method for MRD detection in these hematologic malignant tumors. However, this technique has some drawbacks that can be overcome by next-generation sequencing (NGS). In this study, NGS is validated as an alternative method for qASO-PCR for MRD detection in both ALL and MM. MRD results obtained by NGS and qASO-PCR were compared in 59 of 39 bone marrow samples of 33 of 14 patients with ALL and MM, respectively. Our results indicate that the use of gBlocks as calibrators makes the NGS approach a powerful tool to quantify MRD. With an input of 400 ng of DNA (corresponding to approximately 7 × 10 4 cells), a limit of detection of 0.01% can be achieved. The specificity of the NGS-MRD technique was 100%, and a correlation with qASO-PCR for quantifiable MRD results of 0.93 and 0.91 was found in ALL and MM, respectively. Especially for MM, the higher applicability (100%) of the NGS-MRD protocol, compared with qASO-PCR (57%), was clearly demonstrated. These results demonstrate that NGS is an even better alternative to qASO-PCR.