© 2018 The Author(s) PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells. Remarkably, Parp1−/−;Rad52−/− mice are normal and display prolonged latency of BRCA1-deficient leukemia compared with Parp1−/− and Rad52−/− counterparts. Finally, PARPi+RAD52i exerted synergistic activity against BRCA1-deficient tumors in immunodeficient mice with minimal toxicity to normal cells and tissues. In conclusion, our data indicate that addition of RAD52i will improve therapeutic outcome of BRCA-deficient malignancies treated with PARPi. Sullivan-Reed et al. show that simultaneous treatment with PARP and RAD52 inhibitors exerts dual synthetic lethality in BRCA-deficient tumors. Addition of RAD52 inhibitor should improve therapeutic outcome of BRCA-deficient malignancies treated with PARP inhibitor.