The transcription factor Ets-1 is known to be involved in a broad variety of cellular functions such as cell proliferation, migration, invasion, apoptosis and angiogenesis. In nearly all these reports, the full-length Ets-1 (p51) is commonly considered to be the active form and the role of the Ets-1?VII splice variant (p42) has not been addressed. Therefore, we studied the functional effects of p42 Ets-1 in comparison to p51 Ets-1 expression in a well-characterized mouse fibroblast cell line. Furthermore, the specific role of Ets-1 was evaluated using mouse fibroblasts with a reduced Ets-1 expression caused by RNAi and compared to fibroblasts with a binding inhibition of the whole ETS transcription factor family by stably overexpressing the ETS DNA binding domain as transdominant-negative mutant. Our results demonstrate that p42 Ets-1 has quite different functions and target genes compared to p51 Ets-1 (e.g. TIMP-4, MMP-3, MMP-9, MMP-13). In some cases (e.g. in cytokine expression) p42 Ets-1 is a functional transcription factor which acts in the same manner as a transdominant-negative approach.