The continuing development of ophthalmic steroids has resulted in compounds that have a low tendency to raise intraocular pressure (IOP). Preliminary clinical data have suggested that loteprednol etabonate (LE) 0.5% suspension may not elevate IOP while having promise as a potent topical ophthalmic steroid. This study was designed to evaluate the comparative potential of topical LE and prednisolone acetate (PA) to raise IOP in a population of individuals known to be steroid responders. The study used a double-masked, randomized, single eye, crossover design comparing LE 0.5% and PA 1.0%. Subjects instilled 1 drop of the assigned medication 4 times daily while awake, and follow-up examinations occurred on days 14, 28, and 42. Following a washout period of at least 14 days, subjects entered the second phase of the study, which was identical to the first phase, except that subjects received the alternate study medication. The mean IOP in the LE group increased from 17.4mm Hg at baseline to 21.5mm Hg at day 42 (p > 0.05), while in the PA group the mean IOP increased from 18.1mm Hg at baseline to 27.1mm Hg at day 42 (p < 0.05). There were no serious, severe, or clinically significant events in either group, and LE's effect on IOP was differentiable from that of PA. LE has less effect on IOP when compared to the IOP response induced by PA. LE may become a clinically useful ocular steroid with a favorable IOP-safety profile.