To locate suitable candidates to study the intraocular pressure (IOP) effects of new ocular steroids, healthy volunteers must be challenged with topically applied steroids to verify that such individuals are indeed high “steroid responders”; that is, they respond with IOP elevations of at least 5 mmHg during a 4- to 6-week challenge with the topically applied steroid. We used first-degree offspring of individuals with primary open-angle glaucoma to develop a model to identify high steroid responders to topical ophthalmic prednisolone. We conducted a prospective, randomized, open-label, placebo-controlled study of prednisolone phosphate 1.0% in which 13 subjects received either topical prednisolone phosphate 4 times daily to the right eye and placebo to the left eye, or vice versa. Baseline evaluations occurred on study Day 0, and follow-up examinations were on Days 7, 14, 21, 28, 35, and 42. The medications were administered continuously for 6 weeks or until the IOP rose ≥ 10 mmHg. After the effect of diurnal variation in IOP was taken into account, 4 of the 13 subjects (31%) had a maximum elevation in IOP of 4 mmHg or less, 7 subjects (54%) showed maximum elevations in IOP of 5 to 9 mmHg, and 2 subjects (15%) had a maximum IOP elevation of ≥ 10 mmHg. Thus, a cumulative total of 9 subjects (69%) had IOP elevations of at least 5 mmHg and could be classified as moderate to high steroid responders. This model should become useful as a productive source of subjects for studies evaluating the effect on IOP of new ocular steroids. © 1993, Mary Ann Liebert, Inc. All rights reserved.