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PET/CT with ¹⁸F-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 ¹⁸F-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 ⁶⁸Ga-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 (P < 0.001). CXCR4-directed …