Primary Sjögren's syndrome (pSS) is an autoimmune connective tissue disease characterised by an enhanced lymphoproliferative status, with a greater risk of hesitating in malignant lymphoma. The pathological hallmark of pSS is the mucosa-associated lymphoid tissue (MALT) arising in chronically inflamed tissues, mainly in salivary glands (SG), where inflammation, autoimmunity and lymphoproliferation coexist. In the microenvironment of MALT, the B lymphocyte activating factor (BAFF or BLys) is one of the main actors contributing to B cell survival and hyperactivity in pSS. Due to such a lymphoproliferative background, targeting directly and/or indirectly B lymphocytes has become a cornerstone of developing therapeutic strategies for pSS. The simultaneous and direct targeting of the BAFF axis and of B cells represents a promising new treatment approach for pSS and other immune-mediated diseases, but only investigational at present. Immunobiological evidences support a sequential scheme of administration with belimumab preceding rituximab, aiming to firstly target the microenvironmental BAFF to improve the success of the subsequent depleting treatment in the MALT pathologic tissue with rituximab. In a real pSS case, the sequential therapy with belimumab alone followed by rituximab alone successfully led to a long-term clinical remission of lymphoma and cryoglobulinaemic vasculitis, together with the persistent normalization of B cell hyperactivity and the disappearance of persistent SG swelling and cryoglobulinaemia, which are strong predictors of lymphoma in pSS. Hopefully, further trials will assess if improvement in B-cell targeting will lead to the decrease in SG lymphoid infiltrate as well as to a possible reduction of lymphoma development in pSS.