Resting-state functional MRI (rs-fMRI), coupled with advanced multivariate time-series analysis methods such as Granger causality, is a promising tool for the development of novel functional connectivity biomarkers of neurologic and psychiatric disease. Recently large-scale Granger causality (lsGC) has been proposed as an alternative to conventional Granger causality (cGC) that extends the scope of robust Granger causal analyses to high-dimensional systems such as the human brain. In this study, lsGC and cGC were comparatively evaluated on their ability to capture neurologic damage associated with HIV-associated neurocognitive disorders (HAND). Functional brain network models were constructed from rs-fMRI data collected from a cohort of HIV+ and HIV− subjects. Graph theoretic properties of the resulting networks were then used to train a support vector machine (SVM) model to predict clinically relevant parameters, such as HIV status and neuropsychometric (NP) scores. For the HIV+/− classification task, lsGC, which yielded a peak area under the receiver operating characteristic curve (AUC) of 0.83, significantly outperformed cGC, which yielded a peak AUC of 0.61, at all parameter settings tested. For the NP score regression task, lsGC, with a minimum mean squared error (MSE) of 0.75, significantly outperformed cGC, with a minimum MSE of 0.84 (p < 0.001, one-tailed paired t-test). These results show that, at optimal parameter settings, lsGC is better able to capture functional brain connectivity correlates of HAND than cGC. However, given the substantial variation in the performance of the two methods at different parameter settings, particularly for the regression task, improved parameter selection criteria are necessary and constitute an area for future research.