Class switch DNA recombination (CSR) diversifies the biological effector functions of antibodies and is critical for the maturation of the antibody response. This process is initiated by AID-mediated introduction of double-strand DNA breaks (DSBs) in the upstream and downstream switch (S) regions that will be recombined as effected by intervention of Ku70/Ku86 and the non-homologous end joining (NHEJ) DNA repair pathway. However, Ku-deficient B cells undergo CSR, albeit at a reduced rate, suggesting the involvement of other DNA repair mechanisms. We have demonstrated that B cell deficiency of Rad52, a critical component of the homologous recombination (HR) DNA repair pathway, resulted in increased CSR. Conversely, enforced Rad52 expression impaired CSR. This elevation of CSR in Rad52−/− B cells was associated with increased recruitment of Ku70/Ku86 to S region DSB ends. Indeed, Rad52 competed with Ku70/Ku86 for binding to blunt and staggered DSB ends, as shown by in vitro competition using purified Rad52 and Ku70/Ku86 molecules, and chromatin immunoprecipitation (ChIP) assays involving anti-Rad52 antibody (Ab) and anti-Ku70/Ku86 monoclonal antibody (mAb). In Rad52−/− B cells, the increased role of Ku70/Ku86 in S region recombination was emphasized by decreased occurrence of microhomologies in Sμ-Sα and Sμ-Sγ1 junctions, decreased inter-chromosomal c-Myc/IgH translocations and reduced intra-Sμ recombination. Our findings demonstrate that Rad52 binds to S region DSB ends to facilitate a Ku-independent repair pathway, which favors intra-switch (S) region re-joining and can also resolve inter-switch (S) region DSBs, possibly as part of an alternative NHEJ pathway.