Rifampin is recommended as a prophylactic treatment for intimate contacts of young children who develop invasive infections with Haemophilus influenzae type B (Hib). A 4-day course of rifampin (20 mg/kg of body weight per day, not to exceed 600 mg as a maximum single daily dose) is 95% effective in eradicating pharyngeal colonization with Hib, thus effectively reducing the risk of both associated patients and recurrent illness in index patients less than 2 years old. This study compares rates of eradication of pharyngeal colonization with Hib for 2- and 4-day courses of rifampin therapy. One hundred sixty-three patients with Hib infection were treated at Children's Hospital of Pittsburgh between January 1986 and December 1988; prophylaxis was recommended for 128. Participating families were randomized to receive either 2- or 4-day therapy. Throat swabs were obtained from contacts prior to therapy. Repeat cultures were obtained from colonized contacts 2 days after completing rifampin and again on all contacts 7 to 10 days after completing therapy. Of 68 participating families, 34 received 2-day and 34 received 4-day therapy with rifampin. Twenty-two of 24 colonized contacts in the 2-day group and 17 of 18 in the 4-day group had negative cultures for Hib on follow-up. Two-day therapy with rifampin appears to be as effective as 4-day treatment in the eradication of Hib pharyngeal colonization.