Mef2c contains three alternative exons and generates six Mef2c isoforms in mice. Mef2c α1β isoforms are expressed in neuronal tissues, α2 isoforms are expressed in muscle, and α1 isoforms are expressed in many other tissues. The γ region inclusion and skipped isoforms are present in equal amounts in many tissues. In this study, differences in the transcriptional activities of each tissue-specific isoform of Mef2c in neuronal cells were examined. Using an MEF2-responsive reporter, exon β-dependent transactivation was found in neuronal cells, as well as in other cell lines previously described. Microarray analysis was used to examine the transcriptional activities of each Mef2c isoform and to assess differences in endogenous gene expression induced by the different isoforms. The results showed significant gene expression changes due to overexpression of Mef2c isoforms in both an isoforms-dependent and -independent manner.