Purpose: To determine the intraocular and systemic risk factor differences between a cohort of rapid glaucoma disease progressors and nonrapid disease progressors. Design: Retrospective case-control study. Methods: Setting: Five private ophthalmology clinics. Study Population: Forty-eight rapidly progressing eyes (progression ≥1 dB mean deviation [MD]/year) and 486 non-rapidly progressing eyes (progression <1 dB MD/year). Patients were eligible if they had a diagnosis of glaucoma from their ophthalmologist and if they had greater than or equal to 5 Humphrey visual fields (24-2) conducted. Patients were excluded if their sequential visual fields showed an improvement in MD or if they had greater than 5 dB MD variation in between visits. Patients with obvious neurologic fields were excluded. Observation Procedure: Clinical and demographic data (age, sex, central corneal thickness [CCT], intraocular pressure [IOP], refraction, medications), as well as medical, surgical, and ocular histories, were collected. Main Outcome Measures: Risk factor differences between the cohorts were measured using the independent t test, Wald χ2, and binomial regression analysis. Results: Rapid progressors were older, had significantly lower CCT and baseline IOPs, and were more likely to have pseudoexfoliation, disc haemorrhages, ocular medication changes, and IOP-lowering surgery. They also had significantly higher rates of cardiovascular disease and hypotension. Subjects with cardiovascular disease were 2.33 times more likely to develop rapidly progressive glaucoma disease despite significantly lower mean and baseline IOPs. Conclusion: Cardiovascular disease is an important risk factor for rapid glaucoma disease progression irrespective of IOP control.