Chemotherapy and radiation therapy exert their anti-cancer effects by causing DNA damage, but these treatments can also damage DNA in normal cells resulting in severe side effects such as second cancers in surviving patients. Drugs that antagonize death receptors, Bcl-2 relatives or IAP protein family members trigger direct induction of apoptosis in cells. Since these agents do not rely in DNA damage to stimulate apoptosis, it was hypothesised that they would not provoke mutations in surviving cells, thereby reducing the risk of second cancers. Previously published data and this study showed that death receptor agonist TRAIL induced mutations in surviving cells, and its mutagenic activity was caspase-dependent. To investigate if other classes of direct apoptosis inducers, such as BH3 mimetic and SMAC mimetics, also exhibited mutagenic activity, techniques to detect DNA damage (γH2AX and comet assays) and mutation in surviving cells (HPRT assay) were employed in cell line model systems. Exposure to the BH3 mimetic ABT-737, or SMAC mimetics AT-406/LCL161, did not induce mutations in surviving cells at physiologically relevant doses. This study provides hope that treatment with BH3 mimetic ABT-737, or SMAC mimetics may not cause mutation related side effects in cancer survivors, which is observed in cancer patients treated with DNA damaging therapies.