The effect of flurbiprofen on the corneal penetration of phenylephrine was investigated using isolated albino rabbit corneas mounted in the Ussing diffusion chamber. The corneal penetration of phenylephrine was increased 5–11 times by 4–16 mM flurbiprofen. Such an increase in the corneal penetration of phenylephrine by flurbiprofen appeared to correlate with the increase in the lipophilicity of phenylephrine by flurbiprofen due to ion pair formation. The magnitude of increase at 16 mM flurbiprofen was 2.4 times less than that afforded by 0.5% EDTA and 16.3 times less than that afforded by deepithelizing the cornea. Since flurbiprofen also increased the corneal penetration of benzoic acid and sorbitol with which it cannot form ion pairs, increased lipophilicity of phenylephrine due to ion pair formation with flurbiprofen was unlikely to be the only mechanism that enhanced corneal penetration. An additional mechanism under our experimental conditions of prolonged exposure of the cornea to the phenylephrine-flurbiprofen combination was lowering of the barrier function of the corneal epithelium by concentrations of flurbiprofen greater than that used therapeutically.