Three distinct methodologies have been used to assess corneal oxygen supply during contact lens wear–oxygen transmissibility (Dk/L), equivalent oxygen percentage (EOP), and corneal swelling. To examine the interrelation among these methodologies, we measured the EOP and the amount of corneal swelling in response to a set of contact lenses of a range of Dk/L values on 10 subjects. We also measured the corneal swelling response after exposure to gas mixtures of 0.00, 1.01, 2.65, 5.13, and 10.3% oxygen concentration (balance nitrogen). Analysis of covariance showed that the relation between corneal swelling and EOP during lens wear was significantly different from the relation between corneal swelling and oxygen concentration after exposure to the gas mixtures, leading to different estimates of the minimum oxygen tension required to avoid corneal swelling (18.0% for the EOP technique vs. 10.9% for the gas mixtures). This discrepancy may be explained in terms of the underlying assumptions of the various techniques and by consideration of the mechanisms of corneal swelling during contact lens wear. The clinical implication of this result is that an EOP of 18% should be used as the basis for the development of a daily wear contact lens that provides an “edema-free” response.