The prevalence of alcohol misuse increased substantially over a decade in adults, particularly in those aged 65 years or older. Ramifications for brain structural integrity are significant, especially in older adults. To combine cross-sectional, longitudinal data to test age-alcoholism interactions and examine the association between prevalent comorbidities (drug dependence and hepatitis C virus [HCV] infection) and cortical volume deficits in alcohol dependence. During 14 years, 826 structural magnetic resonance images were acquired in 222 individuals with alcohol dependence and 199 age-matched control participants (aged 25-75 years at initial study), parcellated with a common atlas, and adjusted for brain volume. Longitudinal data were available on 116 participants with alcoholism and 96 control participants. DSM-IV criteria determined alcohol and drug diagnoses; serology testing determined HCV status. The study was conducted at SRI International and Stanford University School of Medicine from April 11, 2003, to March 3, 2017. Magnetic resonance imaging-derived regional cortical volumes corrected for supratentorial volume and sex. Of the 222 participants with alcoholism, 156 (70.3%) were men; mean (SD) age was 48.0 (10.0) years; the mean age for the 199 control participants was 47.6 (14.0) years. Participants with alcohol dependence had volume deficits in frontal (t = -5.732, P < .001), temporal (t = -3.151, P = .002), parietal (t = -5.063, P < .001), cingulate (t = -3.170, P = .002), and insular (t = -4.920, P < .001) cortices; deficits were prominent in frontal subregions and were not sex dependent. Accelerated aging occurred in frontal cortex (t = -3.019, P < .02) and precentral (t = -2.691, P < .05) and superior gyri (t = -2.763, P < .05) and could not be attributed to the amount of alcohol consumed, which was greater in younger-onset than older-onset participants with alcoholism (t = 6.1191, P < .001). Given the high drug-dependence incidence (54.5%) in the alcoholism group, analysis examined drug subgroups (cocaine, cannabis, amphetamines, opiates) compared with drug-dependence-free alcoholism and control groups. Although the alcohol plus cocaine (t = -2.310, P = .04) and alcohol plus opiate (t = -2.424, P = .04) groups had smaller frontal volumes than the drug-dependence-free alcoholism group, deficits in precentral (t = -2.575, P = .01), supplementary motor (t = -2.532, P = .01), and medial (t = -2.800, P = .01) volumes endured in drug-dependence-free participants with alcoholism compared with control participants. Those with HCV infection had greater deficits than those without HCV infection in frontal (t = 3.468, P = .01), precentral (t = 2.513, P = .03), superior (t = 2.533, P = .03), and orbital (t = 2.506, P = .03) volumes, yet total frontal (t = 2.660, P = .02), insular (t = 3.526, P = .003), parietal (t = 2.414, P = .03), temporal (t = 3.221, P = .005), and precentral (t = 3.180, P = .01) volume deficits persisted in the uninfected participants with alcoholism compared with control participants with known HCV status. Drug dependence and HCV infection compounded deleterious effects of alcohol dependence on frontal cortical volumes but could not account for the frontally distributed volume deficits in the drug-free participants with alcoholism. We speculate that age-alcohol interactions notable in frontal cortex put older adults at heightened risk for age-associated neurocompromise even if alcohol misuse is initiated later in life.