PurposeTo compare the effects of ciclosporine A (2%) eye drop and tacrolimus (0.03%) eye ointment on children with vernal keratoconjunctivitis (VKC) who were not responding to corticosteroid eye drops. MethodsA prospective comparative study was carried out on children who were diagnosed with refractory VKC at the ophthalmology clinic in Benha University, Delta area, Egypt, during the period from October 2019 to February 2020.ResultsFifty-nine patients completed this study. Regarding the individual symptom score, redness, burning, photophobia, and foreign body sensation were significantly reduced in the tacrolimus group compared to those in the ciclosporine A group during the 1st week (p < 0.05). Moreover, the tacrolimus group showed a statistically significant reduction in burning and foreign body sensation at the 4th week (both p = 0.032), and in redness and burning sensation at the 12th week compared to those in the ciclosporine A group (p = 0.005 and 0.048, respectively). The tacrolimus group showed significantly lower mean scores for tarsal conjunctival papillary hypertrophy at the 1st week and 12th week (p = 0.037 and 0.046, respectively), and for punctate erosion and cobblestone papillae at the 1st week (p = 0.029 and 0.037, respectively) than the ciclosporine group. Failure of treatment was observed in 6 patients (19.35%) in the ciclosporine A group and in 5 patients (17.85%) in the tacrolimus group. No serious side effects were detected in any group.ConclusionA higher reduction in inflammatory symptoms and signs as well as compliance with tacrolimus 0.03% eye ointment than with ciclosporine A 2% eye drops was observed. Moreover, long-term medication for refractory cases is needed to control inflammation. Overall, our finding suggested that ciclosporine A eye drops and tacrolimus eye ointment could be considered as corticosteroid-sparing drugs in the management of children with refractory VKC.