Abstract Introduction Onodi cells are the most posterior ethmoid air cells and extend superolateral to the sphenoid sinus. These cells are also intimately related with the sphenoid sinus, optic nerve, and carotid artery. Radiologic evaluation is mandatory to assess for anatomic variations before any treatment modalities related to the sphenoid sinus. Objective To evaluate the effect of Onodi cells on the frequency of sphenoiditis. Methods A retrospective analysis was performed in 618 adult patients who underwent high-resolution computed tomography between January 2013 and January 2015. The prevalence of Onodi cells and sphenoiditis was evaluated. Whether the presence of Onodi cells leads to an increase in the prevalence of sphenoiditis was investigated. Results Onodi cell positivity was observed in 326 of 618 patients and its prevalence was found to be 52.7%. In the study group, 60.3% (n = 73) were ipsilaterally (n = 21) or bilaterally (n = 52) Onodi-positive, whereas 39.7% (n = 48) were Onodi-negative (n = 35) or only contralaterally Onodi-positive (n = 13). Of the control group, 48.3% (n = 240) were Onodi-positive and 51.7% (n = 257) were Onodi negative. The co-existence of Onodi cells ipsilaterally was observed to increase the identification of sphenoiditis 1.5-fold, and this finding was statistically significant (p < 0.05). Conclusion The prevalence of sphenoiditis appears to be higher in patients with Onodi cells. However, it is not possible to state that Onodi cells are the single factor that causes this disease. Further studies are needed to investigate contributing factors related to sphenoiditis.