Rifampin prophylaxis (20 mg/kg once daily for four days) was used in close contacts of children with Haemophilus influenzae type b (HIB) disease. Two hours after a dose, the concentration of rifampin in serum and saliva exceeded the minimum bactericidal concentrations of organisms obtained from four of the carriers. In both a randomized prospective and an open study, nasopharyngeal carriage was eradicated in 37 (95%) of 39 contacts. No cases of serious H influenzae disease occurred in four to six months of follow-up. At the dose and treatment schedule used, rifampin was safe and effective for eradication of HIB carriage.