MXenes are among the most diverse and prominent 2D materials. They are being explored in almost every field of science and technology, including biomedicine. In particular, they are being investigated for photothermal therapy, drug delivery, medical imaging, biosensing, tissue engineering, blood dialysis, and antibacterial coatings. Despite their proven biocompatibility and low cytotoxicity, their genotoxicity has not been addressed. To investigate whether MXenes interfere with DNA integrity in cultured cells, we loaded the cells with MXenes and examined the fragmentation of their chromosomal DNA by a DNA comet assay. The presence of both Ti3C2Tx and Nb4C3Tx MXenes generated DNA comets, suggesting a strong genotoxic effect in murine melanoma and human fibroblast cells. However, no corresponding cytotoxicity was observed, confirming that MXenes were well tolerated by the cells. The lateral size of the MXene flakes was critical for developing the DNA comets; submicrometer flakes induced the DNA comets, while larger flakes did not. MXenes did not induce DNA comets in dead cells. Moreover, the extraction of the chromosomal DNA from the MXene-loaded cells or mixing the purified DNA with MXenes showed no signs of DNA fragmentation. Unconstrained living MXene-loaded cells did not show cleavage of the DNA with MXenes under electrophoresis conditions. Thus, the DNA comet assay showed the ability of submicrometer MXene particles to penetrate living cells and induce DNA fragmentation under the applied field. The most probable mechanism of DNA comet formation is the rotation and movement of submicrometer MXene flakes inside cells in an electric field, leading to cleavage and DNA shredding by MXene's razor-sharp edges. Under all other conditions of interest, titanium- and niobium-carbide-based MXenes showed excellent biocompatibility and no signs of cytotoxicity or genotoxicity. These findings may contribute to the development of strategies for cancer therapy.