We describe a case of immune reconstitution inflammatory syndrome (IRIS) secondary to reactivation of Mycobacterium tuberculosis in an HIV-infected patient with a high CD4+ cell count, who presented with a generalized seizure 6 weeks after starting antiretroviral therapy (ART). In our patient, the inflammatory response resulted in radiological features of neurological, pulmonary, and lymph node (LN) tuberculosis- (TB) IRIS, without the typical symptoms. Diagnosis was confirmed by LN biopsy and acid-fast bacilli (AFB) culture of LN and sputum. Treatment with isoniazid, rifabutin, ethambutol, and pyrazinamide was started in addition to continuation of ART. To our knowledge, we describe the first case of an atypical clinical presentation of an unmasking reaction of disseminated TB-IRIS in an HIV infected patient without acquired immune deficiency syndrome (AIDS), with restoring immunity during ART. Clinical and radiological predictors of TB-IRIS in co-infected patients starting ART are therefore essential in anticipating complications and facilitating expeditious management and prompt therapy.