Enfuvirtide is the first member of the fourth class of antiretroviral drugs to become available. We present a case report of a human immunodeficiency virus (HIV)-positive patient with mild renal impairment who developed severe renal impairment secondary to tenofovir therapy while receiving enfuvirtide. Because the patient's pharmacokinetic profile was not significantly altered, compared with that of HIV-infected patients with normal renal function, no dose modifications were required.