Cladophialophora bantianum, a dematiaceous fungus with dark pigmented hyphae, is a rare cause of central nervous system (CNS) infection. This aggressive mold has a high mortality rate, primarily related to its poor response to currently available antifungal therapy. In this article, we report a 74-year-old immunocompromised man who presented with left-sided weakness, sensory deficit, and an abnormal magnetic resonance imaging (MRI) of the brain, which showed multiple ring-enhancing cerebral lesions. The largest lesion measured 4.6 x 3.9 centimeters and was located within the parietal region. He underwent a stereotactic needle biopsy, revealing a pigmented fungus which subsequently grew Cladophialophora bantiana. The patient failed initial monotherapy with liposomal amphotericin B. Later in the patient's hospital course, Flucytosine and voriconazole were added but there was no significant change in the size of the lesions on a repeat brain MRI performed one month into therapy. Surgical resection of the largest lesion was performed. Nevertheless, he continued to deteriorate and therapy was withheld per family request.