Human meconium components were separated into a water-methanol soluble phase containing mainly proteins and bilirubin and a chloroform soluble phase containing free fatty acids, triglycerides and cholesterol. Various amounts of original meconium, the water-methanol soluble fraction or the chloroform soluble fraction were added to standard suspensions of porcine surfactant (Curosurf). In a pulsating-bubble or Wilhelmy-balance system, meconium and its subfractions inhibited surfactant activity, but the chloroform soluble fraction had the highest specific inhibitory activity. Original meconium in saline (130 or 65 mg/ml) was instilled into the airways of ventilated near-term newborn rabbits (dose 6 ml/kg). Lung-thorax compliance was reduced by 38% in animals aspirating the higher dose and by 27% in the low-dose group. Histological sections showed intra-alveolar accumulation of fine meconium particles in experimental animals, but no plugging of larger airways. We conclude that respiratory failure from meconium aspiration may be mediated, in part, by inactivation of surfactant.