Objectives Lesions affecting the lateral recess of the sphenoid sinus are rarely discussed in the literature as a separate entity. This region is difficult to visualize and manipulate through the transnasal routes, especially when extensive pneumatization is present. External approaches to this area involve extensive surgery and are associated with significant morbidity. The objectives of this study are to present our experience with the endoscopic transpterygopalatine fossa approach as a method for exposing and manipulating lesions of the lateral recess of the sphenoid and to illustrate the detailed surgical steps of the procedure. Study Design Retrospective review. Methods Clinical charts of patients who had lesions originating from or extending into the lateral recess of the sphenoid sinus and who were treated at our institutions from September 1995 to June 2002 were retrospectively reviewed. All these patients were managed by the endoscopic transpterygopalatine fossa approach. Results Twelve patients (7 males and 5 females) were included in the study. Lesions included seven cerebrospinal fluid (CSF) leaks and five tumors. One patient with squamous cell carcinoma (SCC) of the sphenoid died of his disease. All CSF leaks were successfully repaired, and benign tumors were removed with good local control through the follow‐up period. Conclusion The endoscopic transpterygopalatine fossa approach is an excellent approach for dealing with lesions of the sphenoid lateral recess.