Mechanisms for loss and gain of introns are elusive. Reported here is a new pattern of intron loss which features a random loss of a single intron in a multiple-intron gene with its neighboring introns remained, which process is defined as intron exclusion. Intron exclusion is reminiscent of removal of a limited stretch of non-homologous sequence in a homologous recombination (HR) triggered by a double strand break (DSB), and therefore lends further evidence for a theory of intron loss through HR between a cDNA and its genomic intron-containing locus. Thus, a model for intron loss is formulated. © 2006 Federation of European Biochemical Societies.