Sedentary behavior (SB; time spent sitting, as distinct from lack of exercise or physical activity) is associated with depression, yet little is known about the relationship between different types of SB (e.g., mentally-passive versus mentally-active) with depression and potential biological mediators of these associations.We used cohort data from the 1958 National Child Development Study (n = 4607; 50.4 % women), conducted in UK, employing the 44 y and 46 y waves as baseline, and the 50 y and 55 y waves as follow-up. Participants reported time spent in TV viewing and watching videos (mentally-passive SB); and, time sitting while doing light activities such as deskwork or driving a car during worktime (mentally-active SB). Depression diagnosis was self-reported during the initial and follow-up waves. Waist circumference, C-reactive protein, and glycated hemoglobin were examined as potential mediators.Mentally-passive SB was associated with incident depression (HR: 1.43; 95%CI: 1.19; 1.71), while there was no association for mentally-active SB. Waist circumference (coefficient: -0.03; 95%CI: -0.05; -0.01; 9.2 %) and C-reactive protein (coefficient: -0.03; 95%CI: -0.04; -0.01; 8.3 %), but not glycated hemoglobin, partly mediated the association for mentally-passive SB.In the relationship of mentally-passive SB with incident depression, the mediating contributions of waist circumference and C-reactive protein point to possible inflammatory-related mechanisms.