GABRA2, the gene encoding the α2 subunit of the GABAA receptor, potentially plays a role in the etiology of problematic drinking, as GABRA2 genotype has been associated with subjective response to alcohol and other alcohol-related reward processes. The GABRA2 gene has also been associated with illicit drug use, but the extent to which associations with drug use are independent of associations with alcohol use remains unclear, partly because most previous research has used a cross-sectional design that cannot discriminate comorbidity at the between-person level and co-occurrence within-persons. The present study used a daily monitoring method that assessed the effects of GABRA2 variation on substance use as it occurred in the natural environment during emerging adulthood. Non-Hispanic European participants provided DNA samples and completed daily reports of alcohol and drug use for 1 month per year across 4 years (N = 28,263 unique observations of N = 318 participants). GABRA2 variants were associated with illicit drug use in both sober and intoxicated conditions. Moreover, the effect of GABRA2 variation on drug use was moderated by an individual’s degree of intoxication. These findings are consistent with recent genetic and neuroscience research, and they suggest GABRA2 variation influences drug-seeking behavior through both alcohol-related and alcohol-independent pathways.