The Myc basic helix-loop-helix zipper domain determines dimerization with Max and binding to the DNA E-box, both of which play a critical role in Myc regulation of growth, proliferation, tumorigenesis, and apoptosis. The mutant basic helix-loop-helix zipper domain, Omomyc, dimerizes with Myc, sequestering it in complexes unable to bind the E-box, and so acting as a potential dominant negative. Consistent with this, Omomyc reverses Myc-induced cytoskeletal disorganization in C2C12 myoblasts. Surprisingly, however, Omomyc strongly potentiates Myc-induced apoptosis in a manner dependent on Myc expression level. Expression analysis of known Myc target genes indicates that Omomyc inhibits transcriptional activation but enhances repression. These findings suggest that Omomyc can selectively trigger apoptosis in cells overexpressing Myc, possibly through the transcriptional repression of specific genes.