Aim Secondary central nervous system (CNS) involvement is a devastating and usually fatal complication of non-Hodgkin's lymphoma (NHL). We aimed to evaluate the incidence of secondary CNS involvement and the value of F-18-FDG PET/computed tomography (CT) imaging in the detection of secondary CNS involvement in patients with NHL. Methods A total of 123 immunocompetent patients (58 men, 65 women; mean age: 56.5 +/- 19.2) with biopsy-proven NHL who underwent F-18-FDG PET/CT for primary staging (n=68) and restaging (n=55) of recurrent disease were reviewed retrospectively. Those with secondary CNS involvement as diagnosed on PET/CT were identified. CNS involvement was confirmed by MRI and cerebrospinal fluid cytology. Results The clinical Ann Arbor stages of the patient population were as follows: stage I - 10 patients; stage II - 44 patients; stage III - 32 patients, and stage IV - 37 patients. PET/CT detected CNS involvement in six patients. The ages of patients with CNS disease ranged from 23 to 68 (mean: 47.2) years. Three patients presented with CNS involvement associated with systemic disease manifestation at initial diagnosis; one patient had isolated CNS relapse and two had relapsed systemic NHL with progression to CNS involvement. Relapse interval was 8-12 months following initial diagnosis. The types of CNS involvement in patients were as follows: parenchymal (n=2), leptomeningeal (n=2), both parenchymal and leptomeningeal (n=1), and pituitary gland involvement (n=1), which is an uncommon manifestation. Median duration of survival was 2.5 months after the diagnosis of CNS involvement. Conclusion The incidence of secondary CNS involvement was 4.4% at initial diagnosis and 5.4% among patients with relapse of lymphoma in our study. PET/CT is a sensitive, objective, and valuable method for the diagnosis of secondary CNS involvement in patients with NHL. In addition, pituitary gland involvement, as a very rare manifestation of secondary CNS lymphoma, has been shown. Nucl Med Commun 34:50-56 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Nuclear Medicine Communications 2013, 34:50-56