Immune reconstitution inflammatory syndrome (IRIS) can be triggered in many ways. IRIS has been recognized during tuberculosis (TB) therapy, especially in patients newly initiated on antiretroviral therapy for HIV or those taken off immunosuppressives such as tumor necrosis factor-alpha inhibitors. However, there are still many triggers of IRIS that are less understood. This case report describes a patient with scrofula that was concerning for TB reactivation, who then had subsequent IRIS. The patient had been consistently using low-dose long-term prednisone for suppression of his polymyalgia rheumatica. It is suspected that the IRIS reaction could be due to an interaction between rifampin and prednisone causing decreased efficacy of its immunosuppressive effects.