CDC has reported previously surveillance data of severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month regimen of rifampin with pyrazinamide (RZ). On the basis of these initial reports, CDC cautioned clinicians in the use of this therapy with advised additional monitoring. To estimate the incidence of RZ-associated severe liver injury and provide more precise data to guide treatment for LTBI, CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI during January 2000-June 2002 and for whom data were reported to CDC through June 6, 2003. This report summarizes the analysis, which found high rates of hospitalization and death from liver injury associated with the use of RZ. On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI. The revised ATS/CDC recommendations described in this report have been endorsed by the Infectious Diseases Society of America (IDSA). Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI. Rifampin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease.