Objective Although depressive symptoms and inflammatory marker C-reactive protein (CRP) have been independently shown to increase the onset of type 2 diabetes (T2DM), whether depressive symptoms modify the effect of inflammatory marker CRP on the onset of T2DM is unknown. Methods In a sample of 3447 participants (25 years old to 74 years old) followed for a mean of 16.7 (±6.1) years (57,540 person-years) from the MONICA/KORA German population-based cohort, we investigated the modification effect of depressive symptoms on the association between standardized highly sensitive CRP levels (mg/L; measured from non-fasting venous blood) and the risk of clinically validated T2DM using stratified Cox Proportional Hazards models adjusted for sociodemographic, lifestyle, Results In the total sample, 13.4% participants developed type 2 diabetes during the follow-up period. In the fully adjusted models, depressive symptoms and increasing CRP levels were independently associated with 1.25 (95% CI =1.01–1.54, p = 0.04) and 1.08 (95% CI = 1.01–1.16, p = 0.02) of increased risk of T2DM, respectively. However, following a significant interaction between depressive symptoms and CRP levels (p = 0.02), analyses stratified according to depressive symptoms revealed that participants with depressive symptoms had an 11% (HR 1.11; 95% CI 1.01-1.19; p< 0.001) increased risk of T2DM, whereas participants without depressive symptoms did not reach significance in their risk of T2DM onset (HR 0.99; 0.89-1.07; p = 0.83). Conclusion The risk of increasing CRP levels on incident T2DM are more pronounced in participants who have depressive symptoms.