We describe a 55-year-old bisexual Belgian man with a multi-drug resistant HIV infection who developed an Immune Reconstitution Inflammatory Syndrome (IRIS) presenting as a mucocele of the frontal sinus, one year after starting a new effective darunavir containing antiretroviral treatment regimen. His CD4+ lymphocyte count had increased from 3 cells/mm3 prior to the start of the latter treatment to 196 cells/mm3 just before he developed the IRIS phenomenon. IRIS is a paradoxical clinical deterioration during highly active antiretroviral treatment (HAART), due to an exaggerated immune-inflammatory reaction. With the increasing numbers of persons living with HIV infection and the increased use of HAART it is expected that in the future more otolaryngological manifestations of IRIS will be detected.