Objective: to assess the utility of 18FDG-PET/CT in the detection of bone marrow (BM) infiltration and the prediction of therapy outcomes in patients with diffuse large B-cell lymphoma (DLBCL). Method: This retrospective study included 111 patients with pathologically confirmed DLBCL. They underwent 18FDG-PET/CT imaging twice at initial staging and 2 to 12 months following completion of the recommended therapy. Results: 18FDG-PET/CT is more accurate than bone marrow biopsy (BMB) for the identification of BM infiltration and exhibited 100% sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy for BM infiltration detection. Patients with avid 18FDG BM uptake has a bad prognosis compared to those with no BM FDG uptake, as it is significantly associated with lower rates of complete metabolic response (CMR) (66% vs. 85.9%; p = 0.019), a higher relapse rate (38.7% vs. 9.1%; p = 0.001), lower four-year relapse-free survival (RFS) (37.4% vs. 90.3%; p = 0.001), a lower five-year overall survival (OS) rate (0% vs. 77.1%; p = 0.034), and a higher death rate (21.3% vs. 6.2%; p = 0.018). Also, patients with axial, multifocal, and diffuse FDG BM uptake have a bad prognosis, lower RFS and OS rates. Conclusion: 18FDG PET/CT imaging provides whole-body mapping for detecting BM infiltration with high SN, SP, and accuracy; it can replace routine BMB in the staging of DLBCL. Avid 18FDG BM uptake is a poor prognostic sign associated with a higher relapse rate and lower rates of CMR and OS.