Alu repeats contribute to genomic instability in primates via insertional and recombinational mutagenesis. Here, we report an analysis of Alu element-induced genomic instability through a novel mechanism termed retrotransposition-mediated deletion, and assess its impact on the integrity of primate genomes. For human and chimpanzee genomes, we find evidence of 33 retrotransposition-mediated deletion events that have eliminated approximately 9000 nucleotides of genomic DNA. Our data suggest that, during the course of primate evolution, Alu retrotransposition may have contributed to over 3000 deletion events, eliminating approximately 900 kb of DNA in the process. Potential mechanisms for the creation of Alu retrotransposition-mediated deletions include L1 endonuclease-dependent retrotransposition, L1 endonuclease-independent retrotransposition, internal priming on DNA breaks, and promiscuous target primed reverse transcription. A comprehensive analysis of the collateral effects by Alu mobilization on all primate genomes will require sequenced genomes from representatives of the entire order.