Diffusion tensor imaging was used to study the combined effects of HIV-infection and alcoholism (ALC) on corpus callosum (CC) integrity in relation to processes of attentional allocation and conflict resolution assessed by a novel Stroop Match-to-Sample task. We tested 16 ALC, 19 HIV, 20 subjects with combined disorder and 17 controls. In ALC, low fractional anisotropy and high mean diffusivity throughout the CC correlated with poor Stroop-match performance, i.e., when the cue-color matched the color of the Stroop stimulus. By contrast, in the two HIV groups DTI relations were restricted to the genu and poor Stroop-nonmatch performance, i.e., when the cue-color was in conflict with the Stroop stimulus color. These results suggest that disruption of callosal integrity in HIV-infection and alcoholism differentially affects regionally-selective interhemispheric-dependent attentional processing. We speculate that callosal degradation in these diseases curtails the opportunity for collaboration between the two hemispheres that contributes to normal performance in HIV or alcoholic patients with higher callosal integrity.