The proliferation deficiency induced by olaparib was synergistic with doxorubicin in LMO2HIGH but not in LMO2LOW DLBCL cell lines and untreated patient-derived primary DLBCL tumors. We also examined the in vivo efficacy of olaparib in DLBCL mice models. Olaparib treatment prolonged survival of mice harboring LMO2HIGH but not LMO2LOW DLBCL xenograft tumors. Olaparib in combination with RCHOP significantly prolonged survival of mice harboring LMO2HIGH DLBCL tumors compared to cohorts treated with either olaparib or RCHOP alone.