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Simple Summary: T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, most often diagnosed in teenagers and young adults. Nowadays, patients are treated with chemotherapy or undergo a hematopoietic stem cell transplantation. This can cause many short- and long-term side-effects and relapse still occurs. Therefore, finding less toxic anti-lymphoma therapies is hoped for. One epidrug of interest is decitabine, a DNA hypomethylating agent that targets the aberrant DNA methylation profile, which previously was FDA-approved for AML and MDS. With the results in this manuscript, we especially hope to provide pre-clinical proof that is necessary to include decitabine as a therapeutic agent in clinical trials for the treatment of T-LBL. Moreover, with the reported downstream effects of decitabine treatment, we hope to further increase the understanding of the working mechanisms of decitabine, which could ultimately result in better treatment protocols and associated biomarkers for T-LBL patients. T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10–20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL. [ABSTRACT FROM AUTHOR]