A 39-year-old man living with AIDS presented with a swollen face. He was found to be HIV infected after presenting with Coccidioides pneumonia 2 years previously and was placed on daily fluconazole and then on highly active antiretroviral therapy. Computed tomography confirmed superior vena cava obstruction secondary to lymphadenopathy. Biopsy confirmed coccidioidomycosis with no evidence of malignancy. To our knowledge, this is the first description of superior vena cave syndrome secondary to coccidioidomycosis and the first description of immune reconstitution inflammatory syndrome involving Coccidioides.