Mucormycosis is a lethal opportunistic fungal infection, described mostly in immunocompromised patients. A comparative cohort study was conducted to compare the evolution of the study group patients with rhino-orbital mucormycosis, in which a therapeutic protocol was instituted, in which the pterygomaxillary fossa is systematically surgically approached and orbital exenteration is performed or not based on the spreading of the infection to the orbital apex or the orbital fissure, with a historical group where these criteria were not applied. Fifteen cases were included, eight in historic group A and seven in the study group B. Medical treatment was provided with control of the underlying disease (amphotericin B and low molecular weight heparin) as well as surgical treatment with extensive debridement including endoscopic ethmoidectomy and exploration of the pterygomaxillary fossa, also performing orbital exenteration only in patients who presented orbital apex syndrome in group B. In group A, there was a mortality rate of 50%, in group B all patients were clinical cured; however, the two patients with hematologic diseases died of complications not related to the fungal infection. With the standardization of a diagnostic and therapeutic protocol, good results in healing and survival of patients can be obtained.