Lysophosphatidic acid (LPA), a small ubiquitous lipid found in vertebrate and non-vertebrate organisms, mediates diverse biological actions. LPA activates mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, and low-molecular-weight G-proteins by binding to multiple LPA receptors (LPA_1–6, and GPR87). We previously demonstrated that colonies of A431 cells, a human epidermoid carcinoma cell line, were dispersed by LPA1 and GPR87 activation. This LPA-induced A431 cell dispersal is accompanied by epithelial-mesenchymal transition (EMT) and is believed to contribute to tumor progression. Endoplasmic reticulum (ER) stress has been implicated in tumor progression and growth. A recent study found that activation of the inositol-requiring enzyme 1α/X-Box binding protein 1 pathway promotes tumor progression and EMT in colorectal carcinoma. In addition, another report indicated that ER stress preconditioning using stress inducers promotes transforming growth factor β1-induced EMT and apoptosis in human peritoneal mesothelial cells. To investigate the effect of ER stress preconditioning on LPA-induced cell dispersal, we analyze the crosstalk between LPA-induced and ER stress-induced cellular responses using A431 cells. Interestingly, preconditioning via tunicamycin, an ER stress inducer, inhibited LPA-induced A431 cell dispersal, whereas thapsigargin, another inducer, promoted cell dispersal. Furthermore, western blot analysis illustrated that LPA-induced p38 MAPK phosphorylation was enhanced by thapsigargin pretreatment but not by tunicamycin. These results indicate that ER stress inducers differentially alter LPA-induced A431 cell dispersal by modifying LPA-related signals.