<p><b>BACKGROUND: </b>Inflammation is implicated as one of many factors related to the development of chronic disease; thus, identifying its modifiable risk factors offers potential intervention targets to reduce risk.</p><p><b>PURPOSE: </b>To investigate whether depression and anxiety symptoms may indirectly affect high-sensitivity C-reactive protein (hs-CRP) and plasminogen activator inhibitor-1 (PAI-1) through sleep duration and adiposity (i.e., percentage body fat and waist circumference).</p><p><b>METHODS: </b>Multiple regression analyses were performed on Hispanic Community Health Study/Study of Latinos Youth (ages 8-16 years) cross-sectional baseline data, which were weighted to adjust for sampling design. Data were collected at a clinical assessment, including fasting blood samples, self-report surveys, and objectively measured anthropometrics.</p><p><b>RESULTS: </b>Adjusting for sociodemographic covariates, depression symptoms were associated with log hs-CRP (β = .011, p = .047) but not PAI-1 (p = .285). Percentage body fat and waist circumference were positively related to depression symptoms (p = .026 and p = .028, respectively) and log hs-CRP (p < .001 for both). When including adiposity in the hs-CRP model, the associations of depression symptoms with hs-CRP were attenuated and became nonsignificant. Monte Carlo confidence intervals (CIs) showed that the indirect effects from depression symptoms to CRP through percentage body fat (95% CI: .0006, .0119) and waist circumference (95% CI: .0004, .0109) were statistically significant.</p><p><b>CONCLUSIONS: </b>Results indicate that the association between psychological distress and inflammation may occur indirectly through adiposity in Hispanic/Latino children. If findings are replicated in causal designs, reducing depression symptoms and adiposity among Hispanic/Latino children may be avenues for primary prevention of inflammation in later years.</p>