Objective To determine whether lamina cribrosa (LC) depth (LCD) and LC thickness (LCT) are associated with a faster rate of progressive retinal nerve fiber layer (RNFL) thinning in primary open-angle glaucoma (POAG). Design Prospective, observational study. Participants One hundred ten eyes diagnosed with POAG (n = 110 patients) in which RNFL thickness had been measured by serial spectral-domain (SD) optical coherence tomography (OCT) for at least 2.5 years. Methods The participants underwent enhanced depth imaging volume scanning of the optic nerve, and circumpapillary RNFL thickness measurements were obtained using SD OCT. The participants were followed up regularly with serial RNFL thickness measurements at 6-month or longer intervals. Lamina cribrosa depth was measured at 7 equidistant planes and LCT was measured at 3 locations (superior midperipheral, midhorizontal, and inferior midperipheral). The rate of RNFL thinning was determined by linear regression of serial OCT RNFL thickness measurements over time. Main Outcome Measures Factors associated with the rate of OCT RNFL thinning. Results A faster rate of RNFL thinning was associated with disc hemorrhage during follow-up (P < 0.001), wider β-zone parapapillary atrophy with Bruch's membrane (P = 0.037), larger global RNFL thickness (P = 0.026), larger LCD (P < 0.001), and smaller LCT (P = 0.002). The association between LCD and the rate of RNFL thinning was explained better using a fractional polynomial model (R2 = 0.223) than a linear model (R2 = 0.134; P = 0.010). Davies' test revealed a statistically significant breakpoint for LCD (489.7 μm), above which a faster rate of global RNFL thinning was associated with a larger LCD. Conclusions A thinner LC and a larger LC displacement had a significant influence on the rate of progressive RNFL thinning.