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Summary Recursive splicing (RS) starts by defining an “RS-exon,” which is then spliced to the preceding exon, thus creating a recursive 5′ splice site (RS-5ss). Previous studies focused on cryptic RS-exons, and now we find that the exon junction complex (EJC) represses RS of hundreds of annotated, mainly constitutive RS-exons. The core EJC factors, and the peripheral factors PNN and RNPS1, maintain RS-exon inclusion by repressing spliceosomal assembly on RS-5ss. The EJC also blocks 5ss located near exon-exon junctions, thus repressing inclusion of cryptic microexons. The prevalence of annotated RS-exons is high in deuterostomes, while the cryptic RS-exons are more prevalent in Drosophila, where EJC appears less capable of repressing RS. Notably, incomplete repression of RS also contributes to physiological alternative splicing of several human RS-exons. Finally, haploinsufficiency of the EJC factor Magoh in mice is associated with skipping of RS-exons in the brain, with relevance to the microcephaly phenotype and human diseases., Graphical Abstract, Highlights • Hundreds of RS-exons in human mRNAs reconstitute cryptic 5ss at exon-exon junctions • EJC represses recursive splicing of RS-exons to preserve transcriptome integrity • RS contributes to physiological alternative splicing • EJC-mediated repression is particularly important in deuterostomes and in the brain, Blazquez et al. demonstrate that hundreds of annotated exons can be skipped from partly spliced transcripts through a mechanism called recursive splicing. Deposition of the exon junction complex represses this mechanism, which is particularly relevant in deuterostomes and the brain, where it can contribute to a microcephaly phenotype and human disease.