There is emerging evidence for a link between sedentary behavior and mental health, although the mechanisms remain unknown. We tested if an underlying inflammatory process explains the association between sedentary behavior and depressive symptoms. We conducted a two year follow-up of 4964 (aged 64.5+/-8.9 years) men and women from the English Longitudinal Study of Ageing, a cohort of community dwelling older adults. Self-reported TV viewing time was assessed at baseline as a marker of leisure time sedentary behavior. The eight-item Centre of Epidemiological Studies Depression (CES-D) scale was administered to measure depressive symptoms at follow-up. At baseline, TV time was associated with C-reactive protein (CRP), adjusted geometric mean CRP values were 2.94 mg/L (<2 h/d TV); 3.04 mg/L (2-4 h/d TV); 3.29 mg/L (4-6 h/d TV); 3.23 mg/L (>6 h/d TV). We observed both a direct association of TV time on CES-D score at follow-up (B=0.08, 95% CI, 0.05, 0.10) and indirect effects (B=0.07, 95% CI, 0.05, 0.08). The indirect effects were largely explained through lack of physical activity, smoking, and alcohol, but not by CRP or body mass index.