Depression is a severe mental disorder often associated with inflammation and metabolic disorders. The C-reactive protein-to-lymphocyte ratio (CLR) may better assess inflammation than C-reactive protein alone, but its relation to depression is unclear. The weight-adjusted waist index (WWI), a central obesity measure, may foster depression via inflammatory responses. This study explores the CLR-depression link and evaluates WWI’s potential mediating role. This study used data from the National Health and Nutrition Examination Survey 2015–2018. A logistic regression model was used to examine the associations between CLR, WWI, and depression, with subgroup analyses assessing effect modifications by sex, age, and other factors. Restricted cubic splines evaluated the linearity of the relationship between CLR and depression, while mediation analysis explored WWI's role in this association. A total of 6024 participants were included. Both CLR (fully adjusted model: OR: 1.095, 95% CI: 1.011, 1.188, p < 0.05) and WWI (fully adjusted model: OR: 1.162, 95% CI: 1.004, 1.345, p < 0.05) showed positive correlations with depression risk. A linear relationship between CLR and depression was found (poverall < 0.05, pnonlinear > 0.05). Subgroup analyses showed stronger associations in males, married/cohabiting individuals, those without heart failure, people aged >60, high school-educated individuals, and middle-income groups. Mediation analysis indicated WWI partially mediated (about 23%) the CLR-depression association. The inflammatory marker CLR is significantly associated with the risk of depression, and WWI partially mediates such an association. This study provides some new insights into the pathogenesis of depression and suggests the potential importance of inflammation and metabolic factors.
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