Radiation pneumonitis (RP) is a serious complication of radiation therapy for thoracic tumors. Lysophosphatidic acid (LPA) and its receptors LPA(1/3) were reported to participate in the processes of inflammation. We tested the hypothesis that LPA and its receptors LPA(1/3), take part in the pathogenesis of RP. In our study, irradiation increased LPA levels in the lung and expression of LPA(1/3). To further determine the role of LPA(1/3), we performed pharmacological knockout of LPA(1/3), by a specific antagonist, VPC-12249. On day 60 post-irradiation, RP was significantly alleviated in a dose-dependent manner in mice treated with VPC-12249, as shown by H&E staining, malondialdehyde (MDA, an indicator of oxidative damage) assay in lung, and concentrations of proinflammatory and profibrotic cytokines in plasma, including IL-1 beta, TNF-alpha, and TGF-beta 1. Additionally, VPC-12249 administration decreased the phosphorylation of I kappa B-alpha (the initial event that activates the NF-kappa B signal way), and expression of TGE-beta 1, CTGF, and alpha-SMA mRNA. Our findings suggest that LPA and LPA(1/3) may play a pivotal role in RP, and LPA-LPA(1/3) may serve as novel therapeutic targets for the treatment of RP.