Cryptococcosis is a life-threatening fungal infection that affects immunocompromised patients, causing predominantly meningoencephalitis and pneumonia. Lymph node involvement is rare and its identification may not be obvious. We report the case of a patient recently diagnosed with AIDS and previously treated for cryptococcal meningitis who developed multifocal cryptococcal disease despite antifungal treatment, expressed as cervical and mediastinal lymphadenitis and constitutional symptoms. The difficulty of the diagnosis was based on the fact that cryptococcal meningitis was resolved after treatment, and the new manifestations were more typical of other conditions such as tuberculosis and malignancy. Final diagnosis was established after fine-needle aspiration cytology of a lymph node with identification. Such cases may be difficult to manage, and the possibility of clinical relapse versus cryptococcal immune reconstitution inflammatory syndrome is discussed. Induction therapy was restarted and maintained for a longer period, and the total duration was based on clinical response.