© 2021 Elsevier LtdCurrently, we need emerging initial data regarding how plastic exposures affect cellular and molecular components and how such interactions will be crucial for human health. We aimed to determine the genotoxic and cytotoxic effects of microplastic (MPs,10-45 μm, polyethylene) on human peripheral lymphocytes by using the cytokinesis-block micronucleus cytome (CBMN) assay, which is a comprehensive method to reveal a range of mechanisms, not only diseases but also response to environmental exposures. We measured micronucleation (MN), nucleoplasmic bridge formation (NPB), and nuclear bud formation (NBUD) in human peripheral blood lymphocytes. We also measured the cytokinesis-block proliferation index (CBPI) to calculate cytostasis, which indicates cytotoxicity in lymphocytes treated with five different MPs concentrations for 48 h. Even lower concentrations of MPs increased the level of genomic instability. We found that the in vitro MP exposure significantly increased MN, NPB, and NBUD frequencies. Since we investigated the effect of larger particles relative to the lymphocytes, mechanic interaction of MPs with cells, the release of monomer and additives from MPs could be suggested as possible mechanisms accounting for increasing genomic instabilities. We did not observe a decrease in the cell proliferation index, indicating a lack of MPs’ cytotoxic potential. To the best of our knowledge, our study is the first to identify MPs’ genotoxic potential in human peripheral blood lymphocytes. We suggested further studies to investigate the genotoxic and cytotoxic potential of smaller plastics and the chronic effect of MP on the human population.