Nasal and paranasal sinus manifestations are among the most common presentations of the acquired immunodeficiency syndrome (AIDS). Several studies cite that as many as 70% of patients with this disease have symptoms referable to the head and neck, including a 30% prevalence of sinusitis. Although the bacteriology of sinusitis in this population is largely considered comparable to that of immunocompetent patients, several opportunistic pathogens have been identified, particularly when T-cell counts are low. This report identifies Acanthamoeba as a potentially fatal cause of rhinosinusitis in immunosuppressed patients. The pathogenesis, diagnosis, and treatment of this rare entity will be discussed and the literature reviewed.