Liposomes containing the acidic phospholipid phosphatidylserine (PS) have been shown to avidly interact with proteins involved in blood coagulation and complement activation. Membranes with PS were therefore used to assess the shielding properties of poly(ethylene glycol 2000)-derivatized phosphatidylethanolamine (PE-PEG 2000) with various acyl chain lengths on membranes containing reactive lipids. The desorption of PE-PEG 2000 from PS containing liposomes was studied using an in vitro assay which involved the transfer of PE-PEG 2000 into multilamellar vesicles, and the reactivity of PS containing liposomes was monitored by quantifying interactions with blood coagulation proteins. The percent inhibition of clotting activity of PS liposomes was dependent on the PE-PEG 2000 content. 1,2-Distearoyl- sn-glycero-3-phosphoethanolamine (DSPE)-PEG 2000 which transferred out slowly from PS liposomes was able to abolish >80% of clotting activity of PS liposomes at 15 mol%. This level of DSPE-PEG 2000 was also able to extend the mean residence time of PS liposomes from 0.2 h to 14 h. However, PE-PEG 2000 with shorter acyl chains such as 1,2-dimyristyl- sn-glycero-3-phosphoethanolamine-PEG 2000 were rapidly transferred out from PS liposomes, which resulted in a 73% decrease in clotting activity inhibition and 45% of administered intravenously liposomes were removed from the blood within 15 min after injection. Thus, PS facilitates the desorption of PE-PEG 2000 from PS containing liposomes, thereby providing additional control of PEG release rates from membrane surfaces. These results suggest that membrane reactivity can be selectively regulated by surface grafted PEGs coupled to phosphatidylethanolamine of an appropriate acyl chain length.