Neurological diseases occur frequently in patients with human immunodeficiency virus (HIV) infection, and include a variety of neuromuscular disorders. On the other hand, only a few cases of motor neuron disease (MND) have been reported to date in HIV-positive patients, even though this neurological complication occurs with a 27-fold greater frequency in these subjects compared with the general population. A retroviral etiology for MND has long been hypothesized, and epidemiological and experimental data suggest a pathogenetic link between HIV infection and MND, because retroviral infections may cause motor neuron damage in both laboratory animals and humans, as a result of various pathways. Furthermore, the introduction of potent, protease inhibitor-based antiretroviral combinations has had a great impact on the natural history of HIV disease and produced a dramatic improvement in some patients with HIV-associated MND, but optimal treatment for this progressive neurological complication has not been well defined. A case of MND in a male HIV-infected patient with significant but transient reversal of neurological symptoms after the use of protease inhibitor-containing antiretroviral regimen is described.