The in vitro activity of cefamandole was determined against 58 isolates of Haemophilus influenzae type b; 47 were β-lactamase-negative (ampicillin-susceptible), and 11 produced β-lactamase (ampicillin-resistant). Ampicillin-susceptible strains were susceptible to cefamandole with a median minimal bactericidal concentration (MBG) of 0.4 μg/ml. Ampicillin-resistant strains had a median MBC of 0.8 μg/ml. Prior studies have documented these concentrations of cefamandole in cerebrospinal fluid in the presence of inflamed meninges. Three children with meningitis due to H. influenzae type b were treated with cefamandole (200 mg/kg per day), including one child with disease due to an ampicillin-resistant strain. All patients showed clinical improvement during therapy. However, sterility of the cerebrospinal fluid was never achieved in two patients during 72–96 hr of therapy with cefamandole. The third patient relapsed with a recurrence of positive cultures during the seventh day of cefamandole therapy. Therefore, cefamandole does not appear to be a useful agent for treatment of meningitis due to H. influenzae type b irrespective of in vitro susceptibility or evidence of penetration into the cerebrospinal fluid.