South Africa is home to more than seven million people living with human immunodeficiency virus (HIV) and a high prevalence of tuberculosis. Human immunodeficiency virus-infected individuals may develop myasthenia gravis (MG), which raises questions regarding their management. An MG database, with 24 years of observational data, was audited for HIV-infected persons. Case reports of MG in HIV-infected persons were reviewed. We identified 17 persons with MG and HIV infection. All had generalized MG with a mean age at onset of 37.8 years. Eleven had acetylcholine receptor antibody-positive MG; one had antibodies against muscle-specific kinase. Six developed MG prior to HIV infection (mean CD4+ 361 cells/mm3); four worsened <6 months of starting antiretrovirals. Eleven developed MG while HIV-infected (mean CD4+ 423 cells/mm3); five presented with mild MG; three in MG crisis requiring rescue therapies (intravenous immune globulin or plasma exchange and/or intravenous cyclophosphamide). Two were diagnosed with HIV infection and MG at the same time. Fifteen required maintenance steroid-sparing immune therapies, predominantly azathioprine, or methotrexate. Plasma HIV viral loads remained below detectable levels on antiretrovirals during immunosuppressant treatment. Over the average follow-up of 6 years, 10 achieved minimal manifestation status, and the remainder improved to mild symptoms. Three cases had tuberculosis before MG, but none developed tuberculosis reactivation on immunosuppressive therapy; one used isoniazid prophylaxis. Herpes zoster reactivation during treatment occurred in one. Conclusions include the following: MG in HIV-infected patients should be managed similarly to individuals without HIV infection; half develop moderate-severe MG; MG symptoms may worsen within 6 months of antiretroviral initiation; safety monitoring must include plasma HIV viral load estimation. Isoniazid prophylaxis may not be indicated in all cases.