OBJECTIVE This study sought to evaluate the efficacy of the isolated use of tacrolimus compared with the combined use of tacrolimus and olopatadine for the treatment of severe vernal keratoconjunctivitis (VKC). METHODS Twenty-one patients with severe VKC were randomized into two groups: one treated with 0.03% tacrolimus ointment combined with 1% olopatadine ophthalmic solution and the other with 0.03% tacrolimus ointment combined with placebo eye drops. The clinical signs and symptoms were graded from 0 to 3, and the efficacy of treatment was determined by the difference between the score at the beginning of treatment and after 30 days. The clinical impression of improvement as perceived by the evaluator and the self-assessment provided by the patient were scored at day 30 of treatment and compared between the groups. RESULTS The scores for symptoms decreased between the assessments in both groups (-1.7±3.9 in the experimental group; -0.6±1.6 in the control group), with no significant difference between groups (P=0.205). The scores for clinical signs decreased between the assessments in the experimental group (-1.1±2.7) and increased in the control group (0.3±0.9) but with no significant differences (P=0.205). There was no significant difference between the groups regarding the self-assessment (P=0.659) and the clinical impression of the evaluator (P=0.387). CONCLUSIONS The isolated use of tacrolimus and the combined use of tacrolimus and olopatadine seems to have the same efficacy, although controlled studies with larger samples are required to confirm this hypothesis.