The serum components of C-reactive protein, lysophosphati-dylcholine, fibrinogen, and fibrinogen proteolytic products have been shown to reduce surface tension-lowering abilities of lung surfactant. The inhibitory effects of these serum components were compared among four different surfactants: natural lung surfactant, a phospholipid mixture that had no surfactant proteins, KL4 surfactant which has a synthetic surfactant protein B (SP-B)-like peptide, and beractant (BER) which has both SP-B and SP-C. The pulsating bubble surfactometer was used to measure the surface tension of these surfactants after the addition of inhibitors. Inhibition of BER and KL4 surfactant was observed with some serum components within 1 min of pulsation, but was reversed after 3 min of pulsation for KL4 surfactant and to a lesser extent with BER. The surface tension of phospholipid mixture alone was significantly increased and did not improve with further pulsations. Natural lung surfactant was least inhibited and was affected only at very high fibrinogen concentrations (5 mg/mL). At identical concentrations of these inhibitors, KL4 surfactant was inhibited less compared with BER. We conclude that the response of a lung surfactant to inhibitory agents may depend on the presence or absence of surfactant-related protein(s) in the surfactant and the concentration of exogenous surfactant used. KL4 surfactant, which has a synthetic peptide in lieu of SP-B, resists inhibition to these serum components more than BER at similar phospholipid concentrations.