Basic helix-loop-helix (bHLH) transcription factors play a pivotal role in the regulation of tumorigenesis, and also in a wide range of other developmental processes in diverse species from yeast to humans. Here we demonstrate for the first time that Ret finger protein (RFP), a member of the TRIM family of proteins initially identified as a recombined transforming gene from a human lymphoma, is a novel interaction partner for four different bHLH proteins (SCL, E47, MyoD and mASH-1), but does not interact with GATA-1 or PU.1. Interaction with SCL required the B-box and first coiled-coil region of RFP together with the bHLH domain of SCL. RFP was able to repress transcriptional activation by E47, MyoD and mASH-1, but not by members of several other transcription factor families. Transcriptional repression by RFP was trichostatin A sensitive and did not involve an Id-like mechanism or ubiquitination with subsequent degradation of bHLH proteins. Instead, our results suggest that bHLH transcription factors are regulated by a previously undescribed interaction with RFP, which functions to recruit HDAC and/or Polycomb proteins and thus repress target genes of bHLH proteins. These results reveal an unexpected link between the bHLH and TRIM protein families.