The effects of long-term extended wear of soft contact lenses on the human cornea were determined by examining 27 patients who had worn a high water content hydrogel contact lens in 1 eye only for an average of 62 +/- 29 months (mean +/- SD). The other eye, which was either emmetropic or amblyopic, acted as a control. The lens-wearing eye showed a 14.8% reduction in epithelial oxygen uptake (P less than 0.001), a 5.6% reduction in epithelial thickness (P less than 0.05), a 2.3% reduction in stromal thickness (P less than 0.05), the induction of epithelial microcysts, and a 22.0% increase in endothelial polymegathism (P less than 0.001). Endothelial cell density was unaffected by extended lens wear. No interocular differences in any of these physiological characteristics were found in a matched control group of anisometropic and amblyopic subjects who did not wear contact lenses. The patients ceased lens wear for up to one month and recovery of corneal function was monitored during this period. Epithelial oxygen uptake and thickness recovered within 33 days of lens removal. The number of microcysts increased over the first 7 days, but decreased thereafter; some microcysts were still present 33 days after lens removal. Recovery from stromal thinning had not occurred after 33 days following lens removal. There was a slight reduction in polymegathism in some patients, but overall this was not statistically significant. These findings establish (1) that the extended wear of hydrogel lenses induces significant changes in all layers of the cornea; (2) that lens wear suppresses aerobic epithelial metabolism, which may compromise the epithelial barrier to infection; and (3) that changes to the stroma and endothelium are long-lasting. Lens-induced effects on corneal physiology can be minimized by fitting lenses that have greater oxygen transmissibility (are thinner), are more mobile, more frequently removed, and more regularly replaced.