The aim of this study was to examine the clinical presentation of patients with malignant lymphoma of the major salivary glands. In a retrospective study, 26 patients with a non-Hodgkin lymphoma (NHL) of the major salivary glands were examined. The results showed a distinct preference for the female gender. Two groups with clinical differences were observed depending on lymphoma manifestation as either extranodal-parenchymal (extranodal) or with intra- or periglandular (nodal) lymph node disease. Differences between these two groups existed with regard to the length of clinical history, recurrent vs continuously progressing symptoms and presentation on ultrasound examination (multiple masses compared to solitary masses). Patients with an extranodal lymphoma always showed disease limited to the affected gland, whereas those patients with a nodal lymphoma presented with stage II or higher (Ann Arbor Classification). In these patients, local recurrence was also five times higher (5/13; 38.4%) than in patients with an extranodal lymphoma (1/13; 7.7%). In 1 patient (7.7%) with extranodal lymphoma, dissemination was observed, compared to 6/13 patients (46.2%) in the group with nodal disease. Seven out of 13 patients (53.8%) with nodal disease died due to lymphoma spread and 1/13 (7.7%) of the patients with extranodal disease. There seem to be distinct clinical differences in the course of patients with NHL of the major salivary glands, depending on extranodal or nodal disease presentation. The histopathological diagnosis, with special recognition of the particular lymphoma pathogenesis, constitutes an important prognostic factor in these patients.