Purpose: To determine which groupings of prognostic factors best explain the rapid progressive retinal nerve fiber layer (RNFL) thinning in patients with primary open-angle glaucoma (POAG). Methods: Optic nerves of 111 POAG patients who were followed for at least 2.5 years, during which the RNFL thickness was measured by serial spectral-domain optical coherence tomography (OCT) were included. Eyes were imaged using enhanced depth-imaging spectral-domain OCT and swept-source OCT angiography to determine the lamina cribrosa curvature index (LCCI), and the presence of a choroidal microvasculature dropout (cMvD), respectively. The rate of RNFL thinning was determined by linear regression of serial OCT RNFL thickness measurements. A regression tree model was used to find groupings of factors that best explain the rate of future RNFL thinning. Results: Disc hemorrhage, larger LCCI, and presence of cMvD were associated with faster global RNFL thinning in the multivariate regression analysis. The regression tree analysis revealed three stratified groups based on the rate of RNFL thinning, divided by the LCCI and the presence of cMvD. Eyes with LCCI ≥11.87 had the fastest RNFL thinning (−2.4 ± 0.8 μm/year, mean ± SD). Among eyes with LCCI <11.87, the presence of cMvD was the strongest factor influencing faster RNFL thinning (−1.5 ± 0.8 μm/year). Eyes with LCCI <11.87 and without a cMvD exhibited the slowest RNFL thinning (−0.8 ± 0.9 μm/year). Conclusions: Our regression tree model demonstrated that larger LCCI, and then the presence of cMvD were the first and second strongest prognostic factors for faster progressive RNFL thinning. Further studies may be needed to confirm these findings.