The purpose of our study was to verify the efficacy of prolonged cycles of 1% topical cyclosporine in improving severe form of vernal keratoconjunctivitis (VKC) in childhood and investigate for factors affecting the response to therapy. We conducted an open trial involving 197 children with severe VKC, who received topical cyclosporine 1% for 4 months. Ocular subjective symptoms (SS) and objective signs (OS) were scored in all children at entry, 2 wks and 4 months. Skin prick tests and microscope endothelial cells evaluation were also performed; serum immunoglobulin E and cyclosporine levels were assessed. The mean score values for severity of SS and OS were significantly decreased after 2 wks and 4 months, compared with those at entry (p < 0.001) in all children. Cyclosporine serum levels were neither detectable at the end of therapy, nor were endothelial corneal cells damaged. Patients who started the therapy at the beginning of the disease and/or received long-term regimen of treatment with cyclosporine had a faster improvement of ocular signs and symptoms, compared with all other patients. Our findings suggest that 1% cyclosporine concentration administrated topically at the beginning of the disease and for a long-term period might be the most effective treatment to control symptoms and local inflammation in severe forms of VKC in childhood.