Background This study investigated the prognostic value of diffuse splenic uptake on F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in gastric cancer (GC) patients. Methods A total of 134 pathology confirmed GC patients who underwent PET/CT for staging workups were enrolled. The maximal standardized uptake value (SUVmax) of primary tumor (Tmax), spleen (Smax), and spleen to liver uptake ratio (SLR) were measured. The prognostic value of PET-measured parameters in GC patients for predicting recurrence-free survival (RFS) and overall survival (OS) were assessed. And the relationships of the parameters with hematological and inflammatory parameters were also investigated. Results During follow-up period, 19 patients (14.1%) had disease recurrence and 12 (8.9%) died from GC. In univariate analysis, hematocrit (p<0.001 and p = 0.002), neutrophil to lymphocyte ratio (NLR; p = 0.021 and p = 0.040), AJCC staging (p<0.001 and p<0.001), adjuvant chemotherapy (p<0.001 and p<0.001), Tmax (p = 0.004 and p = 0.005), and SLR (p = 0.005 and p = 0.016) were significant prognostic factors for RFS and OS, whereas platelet to lymphocyte ratio (PLR; p = 0.034) was a significant prognostic factor for RFS. In multivariate analysis, only SLR was an independent prognostic factor for RFS (p = 0.018, adjusted HR = 3.011, 95% CI = 1.207–7.511). SLR were significantly associated with serum hematocrit level (r = -0.256, p = 0.002), PLR (r = 0.362, p = 0.001), and Tmax (r = 0.280, p = 0.001). Conclusion Diffuse splenic uptake on FDG PET/CT was correlated with the level of hematological and inflammatory parameters and was an independent predictor for RFS in GC.