Metastasis contributes to over 90% of cancer-related deaths, and is initiated when cancer cells detach from the primary tumor, invade the basement membrane and enter the circulation as circulating tumor cells (CTCs). While metastasis is viewed as an inefficient process with most CTCs dying within the bloodstream, it is evident that some CTCs are capable of resisting hemodynamic shear forces to form secondary tumors in distant tissues. We hypothesized that nuclear lamins A and C act as key structural components within tumor cells necessary to resist destruction from elevated shear forces of the bloodstream. Herein, we show that, compared to non-malignant epithelial cells, tumor cells are resistant to elevated fluid shear forces in vitro that mimic those within bloodstream, as evidenced by significant decreases in cellular apoptosis and necrosis. Upon knockdown of lamin A/C, tumor cell resistance to fluid shear stress was significantly reduced, with significantly increased cell death compared to parental tumor cell and non-targeting controls. Interestingly, lamin A/C knockdown increased shear stress-induced tumor cell apoptosis, but did not significantly affect cellular necrosis. These data demonstrate that lamin A/C is an important structural component that enables tumor cell resistance to fluid shear stress-mediated death in the bloodstream, and may thus facilitate survival and hematogenous metastasis of CTCs.