PURPOSE. To compare the effect of disc size and disease severity on the Heidelberg Retina Tomograph (HRT) Glaucoma Probability Score (GPS) and the Moorfields Regression Analysis (MRA) for discriminating between glaucomatous and healthy eyes. METHODS. Ninety-nine eyes with repeatable standard automated perimetry results showing glaucomatous damage and 62 normal eyes were included from the longitudinal Diagnostic Innovations in Glaucoma Study (DIGS). The severity of glaucomatous visual field defects ranged from early to severe (average [95% CI] pattern standard deviation [PSD] was 5.7 [5.0-6.5] dB). The GPS (HRTII ver. 3.0; Heidelberg Engineering, Heidelberg, Germany) utilizes two measures of peripapillary retinal nerve fiber layer shape (horizontal and vertical retinal nerve fiber layer curvature) and three measures of optic nerve head shape (cup depth, rim steepness, and cup size) as input into a relevance vector machine learning classifier that estimates a probability of having glaucoma. The MRA compares measured rim area with predicted rim area adjusted for disc size to categorize eyes as outside normal limits, borderline, or within normal limits. The effect of disc size and severity of disease on the diagnostic accuracy of both GPS and MRA was evaluated using the generalized estimating equation marginal logistic regression analysis. RESULTS. Using the manufacturers' suggested cutoffs for GPS global classification (>64% as outside normal limits), the sensitivity and specificity (95% CI) were 71.7% (62.2%-79.7%) and 82.3% (71.0%-89.8%), respectively. The sensitivity and specificity (95% CI) of the MRA result were 66.7% (58.0%-76.1%) and 88.7% (78.5%-94.34%), respectively. Likelihood ratios for regional GPS and MRA results outside normal limits ranged from 4.0 to 10.0, and 6.0 to infinity, respectively. Disc size and severity of disease were significantly associated with the sensitivity of both GPS and MRA. CONCLUSIONS. GPS tended to have higher sensitivities and somewhat lower specificities and lower likelihood ratios than MRA. These results suggest that in this population, GPS and MRA differentiate between glaucomatous and healthy eyes with good sensitivity and specificity. In addition, the likelihood ratios suggest that GPS may be most useful for confirming a normal disc, whereas MRA may be most helpful in confirming a suspicion of glaucoma. Larger disc size and more severe field loss were associated with improved diagnostic accuracy for both GPS and MRA. Copyright © Association for Research in Vision and Ophthalmology.