Objective The aim of this study was to evaluate PET/FDG metabolic parameters in locally advanced GEJC and correlate it with molecular pathological profiles. Methods We retrospectively analyzed data from 66 patients with a histopathological diagnosis of GEJC who had undergone 18 F-FDG PET/CT before surgical resection. Maximum standardized uptake (SUV max), mean standardized uptake (SUV mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor were measured and calculated using the region of interest (ROI) technique. The relationship between metabolic parameters and the Lauren's classification, histologic differentiation, Ki-67 staining and positivity for human epidermal growth factor receptor 2 (HER2), c-Met, and epidermal growth factor receptor (EGFR) were investigated through immunohistochemical (IHC) analyses. Results Of the total 66 patients, significant differences were observed between intestinal and non-intestinal (mixed and diffuse) adenocarcinomas in SUV max (8.23 ± 2.83 vs. 6.29 ± 2.41, P = 0.008), SUV mean (4.85 ± 1.47 vs. 3.93 ± 1.22, P = 0.017), MTV (24.96 cm 3 vs. 8.90 cm 3 ; P = 0.004), and TLG (97.38 cm 3 vs. 37.09 cm 3 , P = 0.005) values. SUV max , MTV, and TLG of moderately differentiated adenocarcinomas were significantly higher than those of the poorly differentiated ones. SUV max was significantly higher in tissues with a higher Ki-67 index or in the c-MET-negative group (P = 0.045, P = 0.036). No significant correlation was found between metabolic parameters and the expression of HER2 or EGFR in GEJC. Conclusion 18 F-FDG PET/CT may be useful for predicting the molecular pathological profiles of GEJC and for determining appropriate therapeutic strategy.