The objective of the present study was to design a novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of a lipophilic drug, cyclosporine A (CsA). A CsA-loaded microemulsion was prepared using castor oil, Solutol HS 15 (surfactant), glycerol and water. This microemulsion was then dispersed in a Kelcogel solution to form the final microemulsion in situ electrolyte-triggered gelling system. In vitro, the viscosity of the CsA microemulsion Kelcogel system increased dramatically on dilution with artificial tear fluid and exhibited pseudo-plastic rheology. In vivo results revealed that the AUC(0-->32 h) of corneal CsA for the microemulsion Kelcogel system was approximately three-fold greater than for a CsA emulsion. Moreover, at 32 h after administration, CsA concentrations delivered by the microemulsion Kelcogel system remained at therapeutic levels in the cornea. This CsA microemulsion in situ electrolyte-triggered gelling system might provide an alternative approach to deliver prolonged precorneal residence time of CsA for preventing cornea allograft rejection.