Vesicle contents-mixing assays were used to study the fusion of a lipid membrane system that was designed to model the sperm plasma membrane. Comparisons were made to a simpler membrane system that was composed of an equimolar mixture of neutral and anionic phospholipids (phosphatidylcholine (POPC) and phosphatidylserine (POPS)). For both membrane systems, fusion was induced by calcium and was significantly enhanced by the presence of poly(ethylene glycol) (PEG) at a low concentration that was insufficient to cause depletion interactions. In particular, the polymer serves to increase the initial burst and subsequent kinetics of calcium-induced fusion. In comparison with the simpler membrane system, the more-complex sperm mimic vesicles are more resistant to fusion, requiring a higher threshold of calcium concentration. This difference in behavior is attributed to the large fraction of cholesterol (30%) in the sperm mimic membranes. We examined the influence of PEG on ion-binding to membranes using a system that was amenable to nuclear magnetic resonance (NMR). The data are consistent with a PEG-induced reduction of the ion residence time on the vesicle surface, suggesting that ion-binding alterations modulate the kinetics of polymer-enhanced vesicle fusion. Our work suggests that it may be possible to use small doses of PEG in conjunction with fusion-altering agents as effective spermicides.