Simple Summary Standardization of flow-cytometric assessment of minimal residual disease in acute lymphoid leukemia (ALL) is necessary to allow concordant multicentric application of the methodology. This is a prerequisite for internationally collaborative trials, such as the AIEOP-BFM-ALL and the ALL IC-BFM trial. We developed and applied a comprehensive training and quality control program involving a large number of international laboratories within the I-BFM consortium to complement standardization of the methodology with an educational component as well as with persistent quality control measures to allow large ALL treatment trials which use multi-laboratory FCM-MRD assessments for risk stratification of pediatric patients with ALL. Monitoring of minimal residual disease (MRD) by flow cytometry (FCM) is a powerful prognostic tool for predicting outcomes in acute lymphoblastic leukemia (ALL). To apply FCM-MRD in large, collaborative trials, dedicated laboratory staff must be educated to concordantly high levels of expertise and their performance quality should be continuously monitored. We sought to install a unique and comprehensive training and quality control (QC) program involving a large number of reference laboratories within the international Berlin-Frankfurt-Munster (I-BFM) consortium, in order to complement the standardization of the methodology with an educational component and persistent quality control measures. Our QC and quality assurance (QA) program is based on four major cornerstones: (i) a twinning maturation program, (ii) obligatory participation in external QA programs (spiked sample send around, United Kingdom National External Quality Assessment Service (UK NEQAS)), (iii) regular participation in list-mode-data (LMD) file ring trials (FCM data file send arounds), and (iv) surveys of independent data derived from trial results. We demonstrate that the training of laboratories using experienced twinning partners, along with continuous educational feedback significantly improves the performance of laboratories in detecting and quantifying MRD in pediatric ALL patients. Overall, our extensive education and quality control program improved inter-laboratory concordance rates of FCM-MRD assessments and ultimately led to a very high conformity of risk estimates in independent patient cohorts.