N-Myc downstream-regulated gene 1 (ndrg1) is up-regulated in N-Myc knockout mouse embryos. The human NDRG family consists of 4 highly homologous members and human Ndrg1 exhibits approximately 94% homology with mouse ndrg1. However, the regulatory mechanism of NDRG1 via Myc repression is as yet unknown. We previously identified human NDRG2 and demonstrated that this gene is transcriptionally down-regulated by Myc via Miz-1-dependent interaction with the core promoter region of NDRG2. Here, we provide evidence that human NDRG1 is regulated by Myc in a manner similar to NDRG2. We found that Ndrg1 expression levels were enhanced as Myc expression declined in differentiated cells, but were down-regulated following Myc induction. The data revealed that both N-Myc and c-Myc can repress human NDRG1 at the transcriptional level. We further determined that the core promoter region of human NDRG1 is required for Myc repression, and verified the interaction of Myc with the core promoter region. However, the presence of the protein synthesis inhibitor cycloheximide could reverse the repression of Myc, indicating the indirect repression of human NDRG1 by Myc. Moreover, we found that c-Myc-mediated repression can be inhibited by TSA, an HDACs inhibitor, which suggests the involvement of HDACs in the repression process. Taken together, our results demonstrate that, in common with NDRG2, human NDRG1 can be indirectly transcriptionally down-regulated by Myc via interaction with the NDRG1 core promoter.