The (1;19)(q23;p13) translocation, leading to the production of the E2A/PBX1 fusion transcript, is one of the most common translocations in pediatric B-lineage acute lymphoblastic leukemia (ALL). It was assumed to be associated with a poor clinical outcome, although intensive therapy and bone marrow transplantation have been shown to be able to overcome the negative prognostic impact. Only few data are available concerning t(1;19)(q23;p13) in adult ALL. In particular, the prognostic significance of this genetic aberration is not yet clear. We describe three cases of adult ALL carrying the t(1;19)(q23;p13), who were all characterized by an aggressive clinical course and short survival, and discuss the molecular features of the disease as recently identified by gene expression profiling.