Purpose: To assess changes in the peripapillary retinal pigment epithelium (RPE) in association with an acute intraocular pressure (IOP) elevation provoked by a dark room prone provocative test (DRPPT). Design: Prospective, comparative clinical observational study. Participants: Nineteen study group eyes (14 individuals) and 26 control eyes (21 patients). Methods: Individuals with normal optic nerve heads (ONHs) underwent a DRPPT in a standardized manner. They were stratified into a study group with an IOP rise of more than 15 mmHg at the end of the DRPPT and a control group with an IOP rise between 2 and 4 mmHg. Before and at the end of the test, the ONH was imaged by spectral-domain optical coherence tomography (OCT). Main Outcome Measures: Morphologic features of the RPE at the peripapillary end of Bruch's membrane. Results: After a mean IOP rise by 32.1 +/- 9.5 mmHg (range, 17-47 mmHg), 18 (95%) eyes in the study group showed a folding or a centrifugal sliding, or both, of the end of the RPE layer on the peripapillary Bruch's membrane. The RPE changes were located most often at the temporal pole of the ONH (16 eyes [89%]), followed by the nasal pole (2 eyes [11%]). The RPE changes were not detected at the inferior or superior disc poles. Some eyes with marked RPE changes showed corresponding changes in peripapillary beta zone on infrared ONH photographs. In 7 eyes of 7 participants with OCT images obtained on the day after the PRPPT, the RPE end moved back to the end of peripapillary Bruch's membrane. The single eye of the study group without exhibiting IOP rise-associated RPE changes showed an interdigitation zone line indistinguishable from Bruch's membrane line on OCT images. None of the control eyes showed RPE changes. The difference in frequency of RPE changes between study and control groups was significant (P < 0.001). Conclusions: Eyes with an acute rise in IOP (>15 mmHg) showed a folding and centrifugal sliding of the peripapillary RPE and, after IOP reduction, centripetal RPE movement. These observations may be of interest to elucidate the pathogenesis of peripapillary atrophy in glaucoma. (C) 2015 by the American Academy of Ophthalmology.