Several odontogenic and non-odontogenic tumors and related lesions affecting the jaws share clinical presentation and imaging appearance. However, all cases have to be approached and treated on an individual basis, based on a reliable anatomic pathology diagnosis. The present paper describes a case of a desmoplastic fibroma, which was misdiagnosed as an odontogenic keratocyst, and spotlights the potential benefit and conclusive role of a second opinion in oral and maxillofacial pathology diagnosis. A brief review of the literature is also provided.