The purpose of this 3-year prospective study is to compare high school-aged subjects, randomized into wearing soft contact lenses and spectacles, in terms of ocular health, refractive status, and self-esteem. This report focuses on ocular response to the lens care systems used through the first 18 months of the investigation. Eighty-four subjects were randomly fitted with either CibaSoft Visitint or CibaSoft-Standard Visitint contact lenses. Three lens care systems, Ciba Vision AOSept Disinfection/Neutralization Solutions (AOSept), Opti-Free Rinsing, Disinfection, and Storage Solution (Opti-Free), and ReNu Multi-Purpose Solution (ReNu), were randomly prescribed to the subjects wearing contact lenses. Limbal congestion, conjunctival hyperemia, corneal staining with fluorescein, corneal edema, and corneal neovascularization were graded at dispensing and at 6-, 12-, and 18-month visits. There were no significant differences among the groups at baseline. At 6 months statistically significant difference (p = 0.0131, Kruksal-Wallis) was found for fluorescein staining of the cornea among the systems. At 12 months significant differences were found for corneal edema (p = 0.0404, Kruksal-Wallis) and neovascularization (p = 0.0315, Kruksal-Wallis) among the systems. At 18 months generalized conjunctival hyperemia was significantly different (p = 0.0234, Kruksal-Wallis) among the systems along with greater limbal congestion (p = 0.0015, Kruksal-Wallis) and neovascularization (p = 0.0238, Kruksal-Wallis). In conclusion, the cornea, limbal vessels and the conjunctiva respond differently to the lens care systems used in this study. Overall, patients using AOSept showed less corneal staining and inflammatory response than patients using ReNu and Opti-Free.