The expression of protein tyrosine phosphatase epsilon (PTPepsilon) was studied in human tissues and blood cells. High mRNA expression was observed in peripheral blood leucocytes, particularly in monocytes and granulocytes which revealed at least four distinct transcripts. In lymphocytes, PTPepsilon expression was induced after 12-O-tetradecanoylphorbol-13-acetate (TPA) or antigen-receptor stimulation, indicating that PTPepsilon plays a role in the events taking place after antigen engagement. Previously, PTPepsilon has been shown to be involved in regulating voltage-gated potassium channel activity, insulin-receptor signalling and Janus kinase-signal transducers and activators of transcription (STAT) signalling. Transfection of cells with different PTPepsilon constructs and activator protein-1 reporter gene indicates that the catalytic activity of PTPepsilon is involved in the regulation of the mitogen-activated protein kinase cascade. In particular, the extracellular signal-regulated kinases (ERK1/2) were shown to be inhibited in both phosphorylation status and enzymatic activity after overexpression of PTPepsilon. Thus, PTPepsilon emerges as a phosphatase with a potential to regulate the ERK1/2 pathway either directly or indirectly through its catalytic activity.