The translocation E26 transforming-specific (ETS) leukaemia (TEL), alias the ETS variant (ETV6), gene is expressed in most human tissues and encodes a transcriptional repressor. The TEL gene is involved in more than 40 different chromosomal translocations associated with haematological malignancies. As little is known about the function of intact TEL, we searched for TEL-interacting proteins by yeast two-hybrid screening. Among the interacting partners, we identified the histone acetyltransferase protein Tip60 [60 kDa trans-acting regulatory protein of HIV type 1 (Tat)-interacting protein]. The interaction was reproduced in vitro, and in mammalian cells we mapped the interaction regions in TEL to the ETS domain and those in Tip60 to the MYST (‘MOZ, Ybf2/Sas3, SAS2 and Tip60’, where MOZ stands for male absent on the first, SAS for something about silencing and Ybf2 for identical with SAS2) region. Detailed analysis of the Tip60 MYST domain by introduction of point mutations revealed that an N-terminal C2HC zinc finger was essential for interaction with TEL. Finally, we showed that Tip60 functions in a reporter system as a co-repressor in TEL-mediated transcription repression.