Purpose To compare on-road driving performance of patients with moderate or advanced glaucoma to controls and evaluate factors associated with unsafe driving. Design Case-control pilot study. Methods A consecutive sample of 21 patients with bilateral moderate or advanced glaucoma from Washington University, St Louis, Missouri and 38 community-dwelling controls were enrolled. Participants, aged 55-90 years, underwent a comprehensive clinical evaluation by a trained occupational therapist and an on-road driving evaluation by a masked driver rehabilitation specialist. Overall driving performance of pass vs marginal/fail and number of wheel and/or brake interventions were recorded. Results Fifty-two percent of glaucoma participants scored a marginal/fail compared to 21% of controls (odds ratio [OR], 4.1; 95% CI, 1.30-13.14; P =.02). Glaucoma participants had a higher risk of wheel interventions than controls (OR, 4.67; 95% CI, 1.03-21.17; P =.046). There were no differences detected between glaucoma participants who scored a pass vs marginal/fail for visual field mean deviation of the better (P =.62) or worse (P =.88) eye, binocular distance (P =.15) or near (P =.23) visual acuity, contrast sensitivity (P =.28), or glare (P =.88). However, glaucoma participants with a marginal/fail score performed worse on Trail Making Tests A (P =.03) and B (P =.05), right-sided Jamar grip strength (P =.02), Rapid Pace Walk (P =.03), Braking Response Time (P =.03), and identifying traffic signs (P =.05). Conclusions Patients with bilateral moderate or advanced glaucoma are at risk for unsafe driving - particularly those with impairments on psychometric and mobility tests. A comprehensive clinical assessment and on-road driving evaluation is recommended to effectively evaluate driving safety of these patients.