Acute epiglottitis, a life-threatening illness, is characterized by the sudden onset and rapid progression of respiratory obstruction. The etiologic agent is almost exclusively Haemophilus influenzae type b (Hib). During the past decade as many as 25% of strains of Hib have been shown to produce beta-lactamase and be resistant to ampicillin. Recommendations for treatment, in addition to the immediate intubation of the airway, include the administration of chloramphenicol in combination with ampicillin. The combination of sulbactam and ampicillin was evaluated in an effort to develop a safer, but equally effective, regimen. Thirty-one infants and children (mean age, three years six months) with documented acute epiglottitis received parenteral sulbactam sodium (30 mg/kg per day) in combination with ampicillin (200 mg/kg per day). Of the 31 subjects, 26 (84%) had Hib isolated from the blood; seven (27%) of the 26 strains of Hib isolated were beta-lactamase-positive. Twenty-five cases (96%) of Hib epiglottitis responded rapidly to treatment. The combination of sulbactam and ampicillin appeared to be an effective and safe alternative to chloramphenicol/ampicillin therapy for acute epiglottitis in infants and children.