The authors evaluated the mydriatic effect of phenylephrine oxazolidine prodrug, a lipophilic sympathomimetic that undergoes hydrolysis to phenylephrine as it passes through the cornea and aqueous humor. Double-masked clinical trials were performed randomizing 66 healthy subjects to receive either the silicone vehicle as a placebo, 10% viscous phenylephrine hydrochloride (HCl), or prodrug in 0.25%, 0.50%, or 1.0% concentrations. A mean horizontal pupillary diameter of 8.8 mm was achieved in 30 minutes in those receiving 1% prodrug versus 6.5 mm obtained at 30 minutes with 10% viscous phenylephrine HCl. Statistically, this difference was highly significant at P less than or equal to 0.0001. There were minimal systemic or ocular adverse effects from any preparation.