c-myc is a well-known proto-oncogene encoding for a transcription factor that needs to be tightly regulated in order to preserve cell homeostasis. The Promyelocytic Leukaemia gene product PML plays an important role in cell growth and survival, and resides in discrete subnuclear structures called Nuclear Bodies (NB). We performed comparative analysis of the expression of 40 Myc target genes and of Myc binding to their regulatory regions both in wild-type and PML knockout cells. We demonstrate that if PML is absent, despite Myc binding to the DNA regulatory sequences is unchanged, the expression profile of several Myc target genes is altered. PML is largely involved in gene regulation, via recruitment of several transcription factors and cofactors to the NB. Consistently, we show that Myc partially localizes to the NB and physically interacts with PML, and that this localization depends on Myc expression levels. As deregulation occurs to both activated and repressed Myc target genes, we propose that PML influences Myc transcriptional activity through a mechanism that involves the control of Myc post-translational modifications.