DNA repeats constitute potential sites for the nucleation of secondary structures such as hairpins and cruciforms. Studies performed mostly in bacteria and yeast showed that these noncanonical DNA structures are breakage-prone, making them candidate targets for cellular DNA repair pathways. Possible culprits for fragility at repetitive DNA sequences include replication and transcription as well as the action of structure–specific nucleases. Despite their patent biological relevance, the parameters governing DNA repeat-associated chromosomal transactions remain ill-defined. Here, we established an episomal recombination system based on donor and acceptor complementary DNA templates to investigate the role of direct and inverted DNA repeats in homologous recombination (HR) in mammalian cells. This system allowed us also to ascertain in a stringent manner the impact of repetitive sequence replication on homology-directed gene repair. We found that nonspaced DNA repeats can, per se, engage the HR pathway of the cell and that this process is primarily dependent on their spacing and relative arrangement (i.e. parallel or antiparallel) rather than on their sequence. Indeed, our data demonstrate that contrary to direct and spaced inverted repeats, nonspaced inverted repeats are intrinsically recombinogenic motifs in mammalian cells lending experimental support to their role in genome dynamics in higher eukaryotes.