Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently emerging disorder characterized by swelling lesions with storiform fibrosis and lymphoplasmacytic infiltration enriched with IgG4-positive plasma cells. IgG4-RSD has been found in multiple organs/ tissues. The diagnosis requires the integration of clinical, serological, imaging, histopathological, and immunohistological features. The 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) enables the acquisition of whole-body images and provides functional information about disease activity. However, its current role in IgG4-RSD is not well established in clinical practice. In our case, we studied a patient with systemic symptoms, submaxillary adenopathy, and imaging explorations that initially guided toward a lymphoproliferative process. However, the differential diagnosis with an autoimmune systemic disease type IgG4 was considered because of elevated levels of serum immunoglobulins. The study was completed with 18F-FDG PET/ CT that not only allowed us to assess the extension disease and to locate the best lesion for biopsy but also allowed us to evaluate the response to treatment and to diagnose the suspicion of recurrence. In this case, PET/CT shows its usefulness in clinical practice.