<p><strong>Background: </strong>Isolated sphenoid sinus disease (ISSD) includes a small cohort of patients evaluated for sinus disease which tend to be diagnostically challenging and may lead to devastating complications. This study aims to evaluate the spectrum of etiological factors and to analyze clinic-radiological characteristics of ISSD<strong> </strong></p><p><strong>Methods: </strong>It is a<strong> </strong>retrospective review of cases of ISSD managed by the department of otolaryngology of a tertiary care medical centre between January 2017 and December 2019. A total of 21 patients were included and their demographic details, co-morbidities, symptomatology, cross-sectional imaging, treatment received and follow-up details were retrieved from medical records for analysis and comparison.</p><p><strong>Results:</strong> The most common diagnoses in our cohort were invasive fungal sinusitis (n=9), chronic non-specific sinusitis (n=7) and allergic fungal sinusitis (n=3) in that order, with mean duration of symptoms 58.2 days, 300 days and 260 days respectively. Cases of invasive disease had a shorter course, more frequent cranial nerve involvement, with radiological features of heterogenous soft tissue densities and bone erosion. Cases of chronic non-specific sinusitis and allergic fungal sinusitis had more long-standing disease with a milder course and less ominous radiological features. Biopsy report from one of the patient’s was that of squamous cell carcinoma while the other patient was diagnosed with a sphenoid mucocoele.</p><p><strong>Conclusions: </strong>ISSD is an uncommon entity in clinical practice with non-specific symptoms and a potential for grave complications. Therefore, the condition must be borne in mind by clinicians and prompt treatment must be initiated.</p><p><strong> </strong></p>