This study evaluated the effects scleral lens wear has on corneal health using fluorometry and in vivo confocal microscopy. No subclinical changes on healthy corneas of young subjects were observed during 3 months of scleral lens wear. This study aimed to evaluate the effects 3 months of scleral lens wear has on the corneal epithelial barrier function, dendritic cell density, and nerve fiber morphology. Twenty-seven neophytes (mean [standard deviation] age, 21.4 [3.9] years) wore scleral lenses of a fluorosilicone acrylate material bilaterally (97 Dk, 15.6 to 16.0-mm diameter) for 3 months without overnight wear. Subjects were randomized to use either Addipak (n = 12) or PuriLens Plus (n = 15) during lens insertion. Measurements of corneal epithelial permeability to fluorescein were performed with automated scanning fluorophotometer (Fluorotron Master; Ocumetrics, Mountain View, CA) on the central cornea of the right eye and the temporal corneal periphery of the left eye. Images of the distributions of corneal nerve fibers and dendritic cells and nerve fibers were captured in vivo with a confocal laser scanning microscope (Heidelberg Retina Tomograph, Rostock Cornea Module; Heidelberg Engineering, Heidelberg, Germany) on the central and inferior peripheral cornea of the left eye. Corneal measurements and imaging were performed at baseline and after 1 and 3 months of lens wear. The corneal permeability values in natural log, dendritic cell densities, and nerve fiber morphology did not significantly change from baseline to 1 and 3 months of lens wear, for both central and peripheral corneal regions (P > .05). Dendritic cell density at the inferior cornea was higher than the central cornea throughout the study (P < .001). No relationships were observed between each outcome measurements and the saline solution groups (P > .05). Scleral lens wear for 3 months on healthy cornea of young subjects did not affect corneal epithelial barrier function, nerve fiber, and dendritic cell densities. Buffered and nonbuffered saline solutions impacted the corneal health in similar ways.