To determine the efficacy of rifampin prophylaxis in eradication of oropharyngeal carriage of Hemophilus influenzae type b and prevention of secondary H influenzae type b disease, we conducted a multicenter placebo-controlled trial among selected persons with invasive H influenzae type b disease. Households and day-care classrooms were randomized so that their members received either rifampin (initially at a dose of 10 mg/kg/dose for two to four days [rifampin-10], but subsequently at 20 mg/kg/dose for four days [rifampin-20]) or placebo. Pretherapy H influenzae type b colonization rates were similar in the treatment groups. Therapy with either rifampin regimen significantly reduced carriage (rifampin-20, 97%; rifampin-10, 63%; placebo, 28%). New acquisition of carriage was also significantly reduced by either rifampin regimen (rifampin-20 or rifampin-10, 2% v placebo, 6%). No rifampin-resistant H influenzae type b isolates emerged after treatment. Four of 765 placebo-treated contacts experienced secondary disease in contrast to zero of 1,112 rifampin-treated contacts. Because chemoprophylaxis of close contacts with rifampin seems to reduce significantly the risk of secondary H influenzae type b disease, we recommend the administration of prophylaxis in households or day-care classrooms where children younger than 4 years have been exposed to the disease.