Chad A Bousman1, Mariana Cherner1, Stephen J Glatt2, J Hampton Atkinson1, Igor Grant1, Ming T Tsuang1, Ian P Everall11Department of Psychiatry, University of California San Diego, La Jolla, California, USA; 2Department of Psychiatry and Behavioral Sciences, and Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse, NY, USAAbstract: The catechol-O-methyltransferease (COMT) Val allele has been linked to executive dysfunction among healthy individuals. The nature of this relationship is unknown in the context of HIV infection and/or methamphetamine (METH) dependence, two conditions that can alter dopaminergic system functioning. We sought to determine if the putative relationship between COMT and executive dysfunction could be observed among individuals with and without HIV-infection and/or METH dependence, and to explore the specificity of this relationship by examining other cognitive domains. Utilizing an existing cohort of 229 men with and without HIV infection and/or METH dependence we found that Met/Met carriers within the HIV-only and control groups, displayed better executive functioning compared to Val/Val and Val/Met carriers. However, this effect was attenuated in the METH-only and comorbid (ie, HIV+/METH+) groups. Examination of other neurocognitive domains were not consistent with effects found for executive functioning. Results support the presumed neuroprotective effect of Met/Met genotype on executive functioning among HIV-only and control groups. Among METH-only and comorbid groups, the slower rate of dopamine clearance conferred by the Met/Met genotype may increase the risk of adverse effects of METH, resulting in comparable executive dysfunction to that of Val allele carriers.Keywords: Val158Met, Endophenotype, Executive Function