Loteprednol etabonate (LE) is a new corticosteroid based on the "soft drug" concept. Contact lens-associated giant papillary conjunctivitis (GPC) was studied as a model for the anti-inflammatory effect of LE. Patients with bilateral GPC were enrolled in a multicenter, randomized, double-masked, placebo-controlled, parallel group comparison of loteprednol etabonate 0.5% ophthalmic suspension and the LE vehicle (placebo). Patients were instructed to instill 1 drop of the test medication into each eye 4 times daily for 4 weeks, and follow-up examinations occurred on Days 2 or 3, 7, 14, 21, and 28 of masked therapy. Of 113 patients enrolled, 110 patients (LE = 55; placebo = 55) completed the study as planned. Patients receiving LE demonstrated significant reduction in the primary ocular signs of GPC (papillae, p < 0.001) and were rated better in the Investigator's Global Assessment (p = 0.017). LE did not elevate intraocular pressure during the study, and ratings for bulbar conjunctival injection and the Patient Opinion Assessment demonstrated statistical trends that favored treatment with LE. LE was well tolerated and was clinically effective for the treatment of GPC.