A 2-month regimen of rifampin and pyrazinamide (2RZ) became an accepted alternative for treatment of latent tuberculosis (TB) after initial studies in HIV-seropositive patients demonstrated safety and efficacy. Once this alternative came into widespread use, however, a number of cases of severe and fatal hepatitis associated with 2RZ were reported. Although the initial experience with HIV-seropositive patients was encouraging, subsequent research demonstrated that the risk of 2RZ-associated hepatitis is considerably greater than the risk of hepatitis associated with isoniazid treatment for latent TB. Updated guidelines now recommend only restricted use of the 2RZ regimen for latent TB, with careful supervision.