A multicenter, randomized, double-masked, parallel-group study compared the long-term efficacy and safety of lodoxamide 0.1% ophthalmic solution and placebo in 118 patients with vernal keratoconjunctivitis. The test drugs were instilled four times daily for 90 days. Lodoxamide 0.1% ophthalmic solution was significantly (P < .05) more effective than placebo in lowering severity scores for epithelial disease and corneal staining, evidence of the superior efficacy of lodoxamide 0.1% ophthalmic solution in reversing the corneal complications commonly associated with moderate to severe vernal keratoconjunctivitis. Additionally, lodoxamide 0.1% ophthalmic solution ameliorated the other key signs of vernal keratoconjunctivitis, including upper tarsal papillae, limbal signs (papillae, hyperemia, and Trantas' dots), and conjunctival discharge. The between-group differences in the relief of symptoms (itching, tearing, and photophobia) were clinically significant but not always statistically significant. Treatment-related adverse events were reported with similar frequency in both treatment groups, and none were serious.