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Alternative splicing of human cystic fibrosis transmembrane conductance regulator (CFTR) exon 9 is regulated by a combination of cis‐acting elements distributed through the exon and both flanking introns (IVS8 and IVS9). Several studies have identified in the IVS8 intron 3′ splice site a regulatory element that is composed of a polymorphic (TG) m (T) n repeated sequence. At present, no cellular factors have been identified that recognize this element. We have identified TDP‐43, a nuclear protein not previously described to bind RNA, as the factor binding specifically to the (TG) m sequence. Transient TDP‐43 overexpression in Hep3B cells results in an increase in exon 9 skipping. This effect is more pronounced with concomitant overexpression of SR proteins. Antisense inhibition of endogenous TDP‐43 expression results in increased inclusion of exon 9, providing a new therapeutic target to correct aberrant …