Treatment with rimantadine of influenza in children and the potential development of resistance in clinical isolates associated with therapy have not been previously studied. We compared rimantadine to acetaminophen therapy in a controlled, double-blind study of 91 children with influenza-like illness. Of 69 children with proven influenza A/H3N2 infection, 37 received rimantadine and 32 received acetaminophen for five days. Children receiving rimantadine showed significantly greater reduction in fever and improvement in daily scores for symptoms and severity of illness during the first three days. Viral shedding also diminished significantly during the first two days but subsequently increased such that by days 6 and 7 the proportion of children shedding virus, as well as the quantity of virus shed, was significantly greater in the rimantadine group. During the seven-day study, of the 22 children in the rimantadine group with serial isolates tested, ten (45.5%) had resistant isolates compared with two (12.5%) of those with serial isolates in the acetaminophen group (P less than .03). Thus, of the total 37 children in the rimantadine group, 27% were found to have resistant isolated compared with 6% in the total group receiving acetaminophen (P less than .04). Furthermore, the mean inhibitory concentration of rimantadine increased with time in the rimantadine group (r = .4, P = .002) but not in the acetaminophen group. Rimantadine therapy, thus, appears to be significantly more effective than acetaminophen in ameliorating the clinical signs and symptoms of influenza in children. Treatment with rimantadine was also associated with increased viral shedding after the medication was discontinued and with the development of resistance in the clinical isolates, the significance of which is unknown.