PET/CT with F-FDG is an integral component in the primary staging of most lymphomas. However, its utility is limited in marginal-zone lymphoma (MZL) because of inconsistent F-FDG avidity. One diagnostic alternative could be the targeting of C-X-C motif chemokine receptor 4 (CXCR4), shown to be expressed by MZL cells. This study investigated the value of adding CXCR4-directed Ga-pentixafor PET/CT to conventional staging. Twenty-two newly diagnosed MZL patients were staged conventionally and with CXCR4 PET/CT. Lesions identified exclusively by CXCR4 PET/CT were biopsied as the standard of reference and compared with imaging results. The impact of CXCR4-directed imaging on staging results and treatment protocol was assessed. CXCR4 PET/CT correctly identified all patients with viable MZL and was superior to conventional staging ( < 0.001). CXCR4-directed imaging results were validated by confirmation of MZL in 16 of 18 PET-guided biopsy samples. Inclusion of CXCR4 PET/CT in primary staging significantly impacted staging results in almost half of patients and treatment protocols in a third (upstaging, = 7; downstaging, = 3; treatment change, = 8; < 0.03). CXCR4 PET/CT is a suitable tool in primary staging of MZL and holds the potential to improve existing diagnostic algorithms.