Purpose: To assess whether a low cerebrospinal fluid pressure (CSF-P) is associated with open-angle glaucoma in eyes with normal intraocular pressure (IOP). Design: Prospective, interventional study. Participants: The study included 43 patients with open-angle glaucoma (14 with a normal IOP, and 29 with an elevated IOP) and 71 subjects without glaucoma. Interventions: All patients underwent standardized ophthalmologic and neurologic examinations and measurement of lumbar CSF-P. Main Outcome Measures: Cerebrospinal fluid pressure and IOP. Results: Lumbar CSF-P was significantly (P < 0.001) lower in the normal IOP glaucoma group (9.5 +/- 2.2 mmHg) than in the high IOP glaucoma group (11.7 +/- 2.7 mmHg) or the control group (12.9 +/- 1.9 mmHg). The trans-lamina cribrosa pressure difference (IOP minus CSF-P) was significantly (P < 0.001) higher in the normal IOP glaucoma group (6.6 +/- 3.6 mmHg) and the high-IOP glaucoma group (12.5 +/- 4.1 mmHg) than in the control group (1.4 +/- 1.7 mmHg). The extent of glaucomatous visual field loss was negatively correlated with the height of the CSF-P and positively correlated with the trans-lamina cribrosa pressure difference. In the control group, CSF-P was significantly correlated with both systolic blood pressure (P = 0.04) and IOP (P < 0.001). The trans-lamina cribrosa pressure difference was not significantly associated with blood pressure (P = 0.97). Conclusions: In open-angle glaucoma with normal IOP, CSF-P is abnormally low, leading to an abnormally high trans-lamina cribrosa pressure difference. Pathogenetically, a low CSF-P in normal-IOP glaucoma may be similar to a high IOP in high-IOP glaucoma. Consequently, the glaucomatous visual field defect is positively correlated with the trans-lamina cribrosa pressure difference and inversely correlated with the CSF-P. In nonglaucomatous subjects, CSF-P, blood pressure, and IOP are significantly associated with each other. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2010; 117: 259-266 (C) 2010 by the American Academy of Ophthalmology.