Chemotherapy resistance in ovarian cancer remains an unsolved problem in caring for women with this disease. We now show that ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) has higher expression in chemoresistant compared with chemosensitive ovarian cancer cell lines. We have designed a novel secondary cell homing assay (SCHA) to test the ability of cells to withstand chemotherapy and form secondary colonies that could form recurrent disease. OCIAD1 upregulated cells had significantly higher secondary colony-forming ability than had OCIAD1 downregulated cells following treatment with paclitaxel. Additionally, 18:1 lysophosphatidic acid (LPA) increases OCIAD1 expression in a time- and dose-dependent manner. LPA stimulates OCIAD1 serine phosphorylation within two hours of stimulation. Transfection of MKK6 increases OCIAD1 expression but nuclear translocation is inhibited. Inhibition of p38 mitogen-activated protein kinase blocks LPA-induced OCIAD1 expression. Cycloheximide treatment of MKK6-transfected cells does not inhibit OCIAD1 expression, suggesting that MKK6 upregulation is not translationally controlled. OCIAD1 downregulation knocks down LPA-induced cell adhesion to collagen I and laminin 10/11 and specifically inhibits cell attachment to alpha2, alpha5, alphaV, and beta1 integrins. Proteomic studies indicate that OCIAD1 is physically attached to alpha actin 4 and beta actin. Thus, OCIAD1 may play a role in cytoskeletal function which can alter sensitivity to paclitaxel. This is the first study to indicate that OCIAD1 is a key player in generating ovarian cancer recurrence; it is functionally controlled by LPA and MKK6 signaling, and inhibition of OCIAD1 could be an important strategy in the management of recurrent ovarian cancer.