Mycobacterium avium-intracellulare (MAI) complex is a common opportunistic infection that generally occurs in patients with a CD4 cell count less than 75. Current recommendations for prophylaxis include using a macrolide once a week, while treatment usually requires a multidrug regimen. Disseminated MAI infections often occur in patients who are not compliant with prophylaxis or their highly active antiretroviral therapy (HAART). Many manifestations of MAI infection are well documented in human immunodeficiency virus (HIV) patients, including pulmonary and cutaneous manifestations, but other unusual manifestations such as pericarditis, pleurisy, peritonitis, brain abscess, otitis media, and mastoiditis are sporadically reported in the infectious diseases literature. This case report is of a 22-year-old female who contracted HIV at a young age and who was subsequently noncompliant with HAART, MAI prophylaxis, and prior treatment for disseminated MAI infection. Unsurprisingly, the patient developed recurrent disseminated MAI infection. The patient's presentation was atypical, as she developed severe otomastoiditis and posterior reversible encephalopathy syndrome. The posterior reversible encephalopathy syndrome was thought to be due to the disseminated MAI infection or to immune reconstitution inflammatory syndrome. The infection was confirmed to be secondary to MAI by culture of the mastoid bone. Microbiological analysis of the MAI strain cultured showed resistance to several first-line antibiotics used for prophylaxis against and treatment of MAI. This was likely due to the patient's chronic noncompliance. Otomastoiditis secondary to MAI is predominantly a pediatric disease and a rare entity in general. It has been reported in three case reports and one case series in pediatric patients, and now in this case report of an adult patient with HIV [corrected]. Improved clinician education in the diagnosis, treatment, and, most important, prevention of MAI and other opportunistic infections is needed. Greater HIV screening, appropriate HAART medication administration, and availability of infectious disease specialists is needed in at-risk populations to help prevent such serious infections. Patient education and greater access to care should serve to prevent medication nonadherence and to enhance affordability of HAART and prophylactic antibiotics.