Summary Background Several studies have suggested that induced tryptophan (TRP) degradation through the kynurenine (KYN) pathway by the enzyme indoleamine 2,3-dioxygenase (IDO) is implicated in the relation between depression and inflammation. We investigated the role of tryptophan degradation in the relationship between inflammatory markers and depressive symptoms in the Netherlands Study of Depression and Anxiety (NESDA) and hypothesized that tryptophan degradation would mediate (part of) this association. Methods 2812 Participants of NESDA were included in this study including 1042 persons with current major depressive disorder (MDD). Assessments of C-reactive protein (CRP), interleukin (IL)-6, tumor-necrosis factor (TNF)-α, KYN and TRP were obtained from fasting blood samples at the baseline assessment. Tryptophan degradation was estimated by calculating the ratio KYN/TRP. Depressive symptoms were measured with the Inventory of Depressive Symptomatology. Results Significant associations between inflammation and depressive symptoms were found for CRP and IL-6, for the total group and the subgroup of patients with current MDD. Adjustment for KYN/TRP did not attenuate these associations. There were no significant indirect effects for CRP on depressive symptoms mediated by KYN/TRP for the whole group ( B = −0.032; 95% CI: −0.103 to 0.028) and for the subgroup of patients with current MDD ( B = 0.059; 95% CI: −0.037 to 0.165). Also IL-6 did not indirectly affect depressive symptoms through KYN/TRP in the total group ( B = −0.023; 95% CI: −0.093 to 0.045) and in the MDD subgroup B = 0.052; 95% CI: −0.019 to 0.144). Finally, no significant relation between depressive symptoms and KYN/TRP was found in the whole group ( β = −0.019, p = 0.311) nor in the subgroup with MDD ( β = 0.025, p = 0.424). Conclusions We did not find indications for tryptophan degradation, measured by KYN/TRP, to mediate the relationship between inflammation and depressive symptoms.