Persistent isolated inflammation of the sphenoid sinus, an entity that is not diagnosed very often, poses a challenge to clinicians and researchers alike. Its features tend to suggest that its etiopathogenesis is different from that of more common forms of chronic rhinosinusitis. We report the case of a 54-year-old woman who had a history of distressing chronic postnasal drip and a globus sensation with opacification of the sphenoid sinus. She was diagnosed with gastroesophageal reflux, and Helicobacter pylori was detected in her gastric contents and in the inflamed mucosa of the sphenoid sinus, as well. Complete symptom relief was achieved only after she had undergone surgical sphenoidotomy and treatment with anti'H pylori medication. We discuss the potential for this ubiquitous gastric bacterium to play a role in at least some forms of chronic sinonasal inflammation.