To evaluate the rate of thinning in ganglion cell-inner plexiform layer (GCIPL) thickness by optical coherence tomography (OCT) in glaucomatous eyes and to use a trend-based approach to determine its diagnostic ability for detecting glaucoma progression. Prospective, observational study. Sixty-five patients with primary open-angle glaucoma with a minimum 3-year follow-up involving serial spectral-domain OCT measurement of GCIPL thickness. Patients were divided into a nonprogressor group (n= 38) and a progressor group (n= 27) on the basis of serial red-free photography or visual field tests. The rates of GCIPL thinning in the global region, affected hemifield, and 6 macular sectors, and the minimum thickness, were determined by linear regression and compared between groups. The area under the receiver operating characteristic curves (AUCs) were calculated for each parameter. The GCIPL thinning rates were compared between affected hemifields and unaffected hemifields. The macular GCIPL thinning rates in the progressor and nonprogressor groups and the ability of the GCIPL thinning rate to diagnose glaucoma progression. The GCIPL thinning rate was significantly faster in progressors than in nonprogressors in the global area (P < 0.001); in the affected hemifield (P= 0.001); in the temporal, vertical, and nasal sectors of the affected hemifield (P= 0.017, 0.032, and 0.030, respectively); and in the minimum GCIPL thickness (P < 0.001). In the temporal sectors, the GCIPL thinning rates were significantly faster in the affected than in the unaffected hemifield (P= 0.013). The best GCIPL parameters were the global (AUC= 0.791), minimum (AUC= 0.755), inferior hemifield (AUC= 0.708), and affected hemifield (AUC= 0.702) thinning rates. The global circumpapillary retinal nerve fiber layer thinning rate correlated significantly with the global and inferotemporal sector GCIPL thinning rates (rho= 0.259 and 0.366, respectively). The GCIPL thinning rate on OCT was significantly faster for patients with glaucoma with progression than for those without progression. The GCIPL thinning rate of the temporal sector was faster in the affected than in the unaffected hemifield, suggesting that the glaucomatous damage may progress locally in a specific sequence. Trend-based analysis of GCIPL thickness on OCT may be useful for assessing glaucoma progression objectively and quantitatively.