We evaluated the in vivo genotoxicity potential of aerosols generated from two commercial nicotine electronic delivery systems (ENDS) products, P1 and P2, with a combined micronucleus (MN) and comet study design based on OECD TG 474 and TG 489. P1 and P2 were found to give positive and equivocal responses in in vitro micronucleus (MN) assays. P1 and P2 were puffed using an intense regimen (110 ml puff volume, 6-second puff duration, and a 30-second interval) to generate aerosols at 3000 µg/L or 4000 µg/L aerosol mass with a mass median aerodynamic diameter of 0.9-1.0 µm and a geometric standard deviation of 1.6. Male Sprague Dawley rats were exposed to filtered air (negative control) or to ENDS aerosols via nose-only inhalation for up to 6 hours/day for four consecutive days. Blood samples were collected immediately after the Day 3 exposure and analyzed for biomarkers of exposure (nicotine, cotinine, and propylene glycol). At necropsy, bone marrow samples were collected for MN evaluation and liver, lung, and nasal tissue samples were collected for the comet assay (DNA breakage). For both P1 and P2, the plasma nicotine, cotinine, and PG levels increased with increasing aerosol exposure duration in the test article-treated groups, with the plasma nicotine concentrations reaching 1240 ± 158 ng/mL and 1260 ± 265 ng/mL, respectively. There were no significant increases in the bone marrow % MN or in the liver, lung, and nasal tissue % Tail DNA (DNA breakage) compared to the negative control group. Therefore, under the test conditions, P1 and P2 aerosols were concluded negative in vivo for genotoxicity risk.