Acute invasive fungal sinusitis (AIFS) is a rare but frequently lethal condition, commonly associated with a high morbidity among those that survive. It has gained recent media attention on account of its increased incidence following infection with (and treatment for) the novel coronavirus. This paper from a team based at the Cleveland Clinic reports the patient characteristics associated with an increased likelihood of a positive biopsy for AIFS among a cohort of patients suspected to have this condition and biopsied from 2010 to 2020, with the intention being to help permit more timely diagnosis. Twenty-six patients were found to have biopsy-proven AIFS. Features significantly associated with an increased chance of a positive biopsy included facial pain (p=0.047), platelet count <50,000 cells/mm3 (p=0.028), low absolute neutrophil count (ANC, p=0.01) and abnormal CT findings, most commonly bilateral sinus opacification (p=0.003). Overall mortality was 88.5%. In this cohort, the greater the interval between biopsy and definitive surgical debridement, the greater the increase in mortality. Recursive partitioning analysis showed that patients with an ANC <700 cells/mm3 and a platelet count <81,000 cells/mm3 had the highest risk for biopsy-proven AIFS. The authors recommend a biopsy of the middle turbinate in patients with these blood test results and a pyrexia of unknown origin for more than two days and/or symptoms of rhinosinusitis, even if CT imaging is negative. This paper highlights blood test parameters associated with an increased risk of a subsequent diagnosis of AIFS, providing a useful adjunct to clinical and radiological assessment for suspected AIFS. Data from this paper also highlight the primary role of surgical debridement in addition to appropriate antifungal medications to ensure the best possible outcome from this devastating condition.