This study aimed to investigate the correlations between diffuse splenic Fluorine-18-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography/computed tomography (PET/CT) and inflammatory markers and to evaluate the prognostic significance of splenic FDG uptake in rectal cancer patients who underwent curative surgery. We retrospectively analyzed the data from 161 patients who underwent splenic FDG PET/CT staging and subsequent curative surgical resection of rectal cancer between July 2006 and September 2014. The spleen-to-liver uptake ratio (S/L ratio) was calculated by dividing the spleen SUVmean by liver SUVmean. We found significant positive correlations between the S/L ratio and neutrophil-to-lymphocyte ratio (P = 0.013) and platelet-to-lymphocyte ratio (P = 0.007). In a Kaplan–Meier analysis, patients with S/L ratio ≤0.815 had a significantly higher recurrence-free survival rate than those with S/L ratio >0.815 (P = 0.028). Also, patients with S/L ratio ≤0.731 had a significantly higher overall survival rate than those with S/L ratio >0.731 (P = 0.036). In multivariate analysis, higher S/L ratio, as well as male, poor differentiation, higher TNM stage, perineural invasion, and larger tumor size, was independently predictive of cancer recurrence (>0.815 vs ≤0.815, hazard ratio [HR]: 2.04, P = 0.046). With regard to OS, S/L ratio was also an independent prognostic factor for death during follow-up (>0.731 vs ≤0.731, HR: 3.81, P = 0.017). Our results show significant correlations between S/L ratio on PET/CT and systemic inflammatory markers. Further, S/L ratio was an independent prognostic factor for predicting recurrence and death in patient with rectal cancer after curative surgery.