There has been much recent interest in lysophosphatidic acid (LPA) signaling through one of its receptors, LPA 1, in fibrotic diseases, but the mechanisms by which LPA-LPA 1 signaling promotes pathological fibrosis remain to be fully elucidated. Using a mouse peritoneal fibrosis model, we demonstrate central roles for LPA and LPA 1 in fibroblast proliferation. Genetic deletion or pharmacological antagonism of LPA 1 protected mice from peritoneal fibrosis, blunting the increases in peritoneal collagen by 65.4 and 52.9%, respectively, compared to control animals and demonstrated that peritoneal fibroblast proliferation was highly LPA 1 dependent. Activation of LPA 1 on mesothelial cells induced these cells to express connective tissue growth factor (CTGF), driving fibroblast proliferation in a paracrine fashion. Activation of mesothelial cell LPA 1 induced CTGF expression by inducing cytoskeleton reorganization in these cells, causing nuclear translocation of myocardin-related transcription factor (MRTF)-A and MRTF-B. Pharmacological inhibition of MRTF-induced transcription also diminished CTGF expression and fibrosis in the peritoneal fibrosis model, mitigating the increase in peritoneal collagen content by 57.9% compared to controls. LPA 1-induced cytoskeleton reorganization therefore makes a previously unrecognized but critically important contribution to the profibrotic activities of LPA by driving MRTF-dependent CTGF expression, which, in turn, drives fibroblast proliferation.—Sakai, N., Chun, J., Duffield, JS, Wada, T., Luster, AD, Tager, AM LPA 1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation.