Background: Cavernous sinus-orbital apex aspergillosis is a rare but serious complication and difficult to diagnose based on clinical and radiological results. This condition is frequently diagnosed at a late stage because of its nonspecific and varying symptomatology, specifically in immuno-supressive patients. Early diagnosis and treatment is the key to prevent more serious central nerves system complications. Methods: We report the case of a 80-year-old man with a 2 month history of retroorbital pain before he developed a subacute cavernous sinus syndrome, with 3th cranial nerve palsy and right-sided painful ophthalmoplegia. Patient was on immune suppression therapy for chronic lymphocytic leukemia. Neuroimaging including CT scan and MRI suggested a malignant tumor involving the sphenoid sinus with extention to cavernous sinus-orbital ape. Results: The diagnosis of aspergillosis was made trans-sphenoidal approach and by histopathological examination. Soon after surgical drainage of the sphenoid sinus and systemic anti-fungal drug therapy, Both retroorbital pain resolved and cavernous sinus syndrome slowly start to recover. Conclusions: This case emphasizes the fact that invasive isolated sphenoid sinus aspergillosis must be considered in the list of lesions causing sinus cavernous syndrome and particularly in immune suppressed patients. Early diagnosis is the key to prevent more serious central nerves system complications.