INTRODUCTION AND OBJECTIVES: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in cervical tumors, correlated with negative clinical outcomes. EGFR may be activated by a diversity of mechanisms including transactivation by G-protein coupled receptors (GPCRs). Studies have also shown that platelet-activating factor (PAF), a pro-inflammatory phospholipid mediator, plays an important role in the cancer progression through its receptor (PAFR), a member of the GPCRs family, either by modulating the cancer cells or the tumor microenvironment. PAF/PAFR- and EGFR-evoked signaling pathways contribute to tumor biology, however, the interplay between them remains uninvestigated in cervical cancer. MATERIAL AND METHODS: Here, we employed cervical cancer cell lines (CASKI and C33A) and The Cancer Genome Atlas (TCGA) to assess the role of EGFR, PAFR and the LPCAT family (enzymes in the PAF synthesis pathway) in the prognosis of cervical cancer patients. cBioportal, a TCGA-based database, was used to perform the gene expression correlation studies and the overall survival studies. PAF was used as PAFR agonist and EGF as EGFR agonist, while WEB2086, cetuximab, PD98059 and LY294002 were used as PAFR, EGFR, MEK-ERK, and PI3K-Akt inhibitors, respectively. qPCR was used to measure gene expression and Western blotting to analyze protein expression and phosphorylation. Cell migration assay, flow cytometry cell death detection, cell viability assay and colony formation assay were performed to analyze the biological importance of the two pathways. RESULTS AND CONCLUSION: A strong positive correlation between the expression of EGFR x PAFR, and EGFR x LPCAT2 was observed in 306 cervical cancer samples. The overexpression of LPCAT2 was significantly correlated with poor overall survival. Activation of EGFR upregulated the expression of PAFR and LPCAT2 in a MAPK-dependent fashion, while PAF showed the ability to transactivate EGFR leading to ERK/MAPK activation, cyclooxygenase-2 (COX-2) induction, and cell migration. The positive crosstalk between the PAF-PAFR axis and EGFR demonstrates an important linkage between inflammatory and growth factor signaling in cervical cancer cells. Finally, combined PAFR and EGFR targeting treatment impaired clonogenic capacity and cell viability of aggressive cervical cancer cells more strongly than each treatment separately. Collectively, we proposed that EGFR, LPCAT2, and PAFR emerge as novel targets for cervical cancer therapy.