A novel cytoplasmic splice variant of the human beta4 integrin subunit has been identified by reverse transcription polymerase chain reaction using mRNA from cultured keratinocytes as the template. This fifth beta4 variant, called beta4E, is expressed in a wide variety of tissues including the epidermis, lung, duodenum, heart, spleen and stomach and in several human epithelial cell lines. The beta4E cDNA contains an insert of 37 base pairs which produces a frame shift in the sequence encoding the beta4 cytoplasmic domain and generates a new stop codon after a stretch of cDNA encoding a unique 114-amino acid peptide. Analysis of the genomic organization at the site of this insertion in the human beta4 gene reveals that beta4E is produced by partial retention of an intron in the final transcript.