When subjected to large hypoosmotic gradients, lipid vesicles swell and rupture, expelling contents in an attempt to reach mechanical equilibrium. To date, the influence of the lipid composition on this leakage process has not been studied. In this paper, we present osmotic leakage data for vesicles made of a series of phosphatidylcholine lipids and show that the lipid composition is an important control parameter in osmotically forced leakage. We also show that current models for the leakage phenomenon fail to predict experimental results and offer an improved model that allows for the possibility of a mixed population of unilamellar and multilamellar vesicles. Finally, we demonstrate that mechanical properties found using the micropipet aspiration method might not be applicable to osmotic swelling experiments utilizing nanometer-scale vesicles.