Anaplastic Large Cell Lymphomas (ALCL) are a clinically and biologically heterogeneous disease including the ALK+ and ALK- systemic forms. While ALK+ ALCL are molecularly characterized and can be readily diagnosed, specific immunophenotypic or genetic features to define ALK- ALCL are missing, and their distinction from other T-Cell Non- Hodgkin Lymphomas (T-NHL) remains controversial. Here, we undertook a transcriptional profiling meta-analysis of 309 cases, including ALCL and other primary T-NHL samples. Pathway discovery and prediction analyses defined a minimum set of genes capable to recognize ALK- ALCL. Application of RT-qPCR in independent data sets from cryopreserved and formalin-fixed paraffin embedded (FFPE) samples validated a three-gene model (TNFRSF8, BATF3, TMOD1) able to successfully separate ALK- ALCL from PTCLNOS, with overall accuracy near 97%. In conclusion, our data justify the possibility to translate RT-qPCR protocols to routine clinical settings as a new approach to objectively dissect T-NHL and to select more appropriate therapeutic protocols.