The landmark Collaborative Initial Glaucoma Treatment Study (CIGTS) demonstrated that while surgery lowers intraocular pressure (IOP) more than medications in eyes with primary open-angle glaucoma (POAG), both treatment modalities confer similar protection against future progression. In CIGTS, data from one study eye of 607 POAG patients were analyzed. In a recent report by Niziol and colleagues, clinical outcomes in non-study fellow eyes have been described, as have correlations of clinical course between study and non-study fellow eyes over seven years of follow-up. Perhaps intuitively, the clinical course of between study and non-study fellow-eye pairs - as measured by the slope of visual field mean deviation over time - was highly correlated (r = 0.73) when both eyes have POAG and receive treatment. Less intuitive is the observation that fewer than half of individuals (47.9%) required treatment in the non-study eye at enrollment: essentially, more than half of CIGTS participants had unilateral POAG at study entry. Further, nearly one-third of participants (31.8%) did not require treatment for POAG in the non-study eye over a seven-year follow-up period. This finding is unlikely to be shaped by the restrictive eligibility criteria defining POAG for study entry, as the current analysis pertains to the clinical decision to treat or not treat the non-study eyes and not to its meeting the study criteria for POAG diagnosis. This finding - that half of POAG patients effectively have unilateral disease at diagnosis and one-third will remain unilateral for > seven years - is contrary to conventional wisdom and worthy of further investigation. One potential ramification of this observation pertains to the pathogenesis of POAG. While the genetic basis of POAG is all but certain, the underlying genetic mechanisms leading to the disease remain incompletely characterized. The fellow-eye discordance of POAG described in this analysis suggests that eye-level (rather than or in addition to individual-level) factors may play an important role in the development of POAG in at-risk individuals.