The risk factors for acquisition of secondary day-care-associated Haemophilus influenzae type b disease were evaluated in a cohort of children in Seattle-King County, Washington; Atlanta; and the state of Oklahoma. During the study period, 129 primary cases were identified in children less than 5 years old who attended day-care facilities. In ten instances (8\%), a secondary case occurred between one and 60 days after a primary case in the same classroom. Risk of secondary disease in classroom contacts was strongly age related: 2.4\% in children 0 to 11 months old, 1.2\% in children 12 to 23 months old, and 0.0\% in children 24 to 59 months old. Controlling for age, children attending day-care more hours per week were more likely to transmit or acquire secondary disease. Risk of secondary disease for children in other classrooms at a center where a case had occurred was not significantly greater than risk of primary disease. Administration of rifampin to classroom contacts of a child with invasive H influenzae was effective in preventing secondary cases (95\% confidence interval for rifampin efficacy, 47\% to 100\%). For children 0 to 23 months old not treated with rifampin, risk of secondary disease was 2.7\% (95\% confidence interval, 1.1\% to 4.3\%), a risk approaching that reported in household contacts.