Rationale <p>Early life stress (ELS) is associated with an increased risk for alcohol consumption and development of alcohol use disorder (AUD). Inflammation may be a sex-dependent link between ELS and alcohol use; however, there is limited evidence to support such an association in individuals with AUD.</p> Methods <p>This secondary analysis utilized cross-sectional mediation to investigate the role of peripheral inflammation in the relationship between ELS and alcohol consumption (i.e., drinks per drinking day (DPDD)) in treatment-seeking individuals with AUD (<i>n</i> = 99; 60&#xa0;M/39 F). A cross-sectional moderated mediation analysis was conducted to test sex as a moderator in the link between ELS and inflammation for the above relationship. ELS was conceptualized as a dichotomous “no-moderate ELS” vs. “high-ELS” predictor.</p> Results <p>High-ELS was associated with higher inflammation (95%CI 0.039,1.558), and higher inflammation was associated with greater DPDD <i>(</i>95%CI 0.024,0.098). A mediation effect emerged where high-ELS influenced greater DPDD through elevated inflammation (<i>ab</i> = 0.044, 95%CI 0.002,0.113). No direct effects between ELS and DPDD emerged (95%CI -0.177,0.108). The interaction between ELS and sex on inflammation was significant for females (95%CI: 0.304,2.719) but not males (95%CI: -0.634,1.270). The mediation relationship between ELS and DPDD through inflammation was significant for females (<i>ab(female)</i> = 0.087, 95%CI: 0.013,0.199) but not males (95%CI: -0.040,0.086).</p> Conclusions <p>Findings suggest that ELS is associated with recent alcohol use through peripheral inflammation in treatment-seeking individuals with AUD and indicate that this pathway is sex-dependent. Inflammation may be a treatment target for individuals with AUD who have experienced ELS, especially females. Clinical Trials Registration: NCT03594435, registered July 11, 2018.</p>