PURPOSE We evaluated three new pixelwise rates of retinal height changes (PixR) strategies to reduce false-positive errors while detecting glaucomatous progression. METHODS Diagnostic accuracy of nonparametric PixR-NP cluster test (CT), PixR-NP single threshold test (STT), and parametric PixR-P STT were compared to statistic image mapping (SIM) using the Heidelberg Retina Tomograph. We included 36 progressing eyes, 210 nonprogressing patient eyes, and 21 longitudinal normal eyes from the University of California, San Diego (UCSD) Diagnostic Innovations in Glaucoma Study. Multiple comparison problem due to simultaneous testing of retinal locations was addressed in PixR-NP CT by controlling family-wise error rate (FWER) and in STT methods by Lehmann-Romano's k-FWER. For STT methods, progression was defined as an observed progression rate (ratio of number of pixels with significant rate of decrease; i.e., red-pixels, to disk size) > 2.5%. Progression criterion for CT and SIM methods was presence of one or more significant (P < 1%) red-pixel clusters within disk. RESULTS Specificity in normals: CT = 81% (90%), PixR-NP STT = 90%, PixR-P STT = 90%, SIM = 90%. Sensitivity in progressing eyes: CT = 86% (86%), PixR-NP STT = 75%, PixR-P STT = 81%, SIM = 39%. Specificity in nonprogressing patient eyes: CT = 49% (55%), PixR-NP STT = 56%, PixR-P STT = 50%, SIM = 79%. Progression detected by PixR in nonprogressing patient eyes was associated with early signs of visual field change that did not yet meet our definition of glaucomatous progression. CONCLUSIONS The PixR provided higher sensitivity in progressing eyes and similar specificity in normals than SIM, suggesting that PixR strategies can improve our ability to detect glaucomatous progression. Longer follow-up is necessary to determine whether nonprogressing eyes identified as progressing by these methods will develop glaucomatous progression. (ClinicalTrials.gov number, NCT00221897).