Immune checkpoint inhibitors (ICIs) combined with chemotherapy have emerged as a new choice for advanced and metastatic gastric cancer (GC) patients. Due to the lack of unified and effective predictive biomarkers, there is an urgent need to find accurate biomarkers. The aim of our study was to explore the prognostic value of the pretreatment D-dimer levels on the effect of immunotherapy combined with chemotherapy in advanced and metastatic GC patients.We retrospectively reviewed 40 advanced and metastatic GC patients receiving programmed death 1/programmed death ligand-1 (PD-1/PD-L1) inhibitors. The optimal D-dimer cut-off value was calculated based on the Youden index for overall survival (OS). The efficacy and prognostic outcomes of ICIs combined with chemotherapy in patients with advanced or metastatic GC were assessed across subgroups stratified by pretreatment D-dimer levels. Univariate and multivariate regression analyses were performed to evaluate the potential prognostic factors for progression-free survival (PFS) and OS.The optimal cut-off value of D-dimer was 0.965 µg/mL, with a sensitivity and specificity of 0.857 and 0.789, respectively, based on the receiver operating characteristic (ROC) curve and Youden index. The low D-dimer group exhibited higher disease control rate (DCR) compared to the high D-dimer group (72.2% vs. 22.7%, P=0.002). The median PFS in the low D-dimer group was 13.6 months, in comparison with 4.4 months in the high D-dimer group (P<0.001). The OS was 8.1 months in the high D-dimer group, whereas the median OS was not reached in the low D-dimer group (P=0.003). Univariate and multivariate Cox analyses indicated that high D-dimer and carbohydrate antigen 19-9 (CA19-9) levels were independent risk factors for PFS and OS.Pretreatment D-dimer level may be an independent predictive biomarker for efficacy and prognosis in advanced and metastatic GC patients receiving first-line immunotherapy combined with chemotherapy.Copyright © 2025 AME Publishing Company. All rights reserved.