Diffuse infiltrative lymphocytic syndrome is a clinical identity that can be part of the spectrum of Human Immunodeficiency Virus infection. It is characterized by sicca symptoms, parotid and lachrymal enlargement and extra-articular manifestations. We report the case of a 60 years old woman with clinical sicca syndrome in association with leukopenia, positive anti-nuclear antibody (ANA) and polyclonal hypergammaglobulinemia. In the follow up the patient developed a mucosa-associated lymphoid tissue pulmonary neoplasm. Furthermore, the clinical surveys revealed human immunodeficiency virus (HIV) positive markers. In this particular case report, we must underline the clinical presentation of a sicca syndrome as a manifestation of the HIV infection, bearing in mind that, frequently, the differential diagnosis from other diseases, namely the Sjögren's syndrome, is a real challenge.