There is evidence that in non-diabetic people depression is associated with an elevation of circulating levels of inflammatory markers. Cross-sectionally, this study examines if high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-18, IL-1 receptor antagonis (IL-1RA), monocyte chemotactic protein (MCP)-1 and adiponektin are associated with depression at baseline in people with diabetes. Longitudinally, this study also analyzes if a significantly improved depression score after a 12 month follow-up was associated with a reduction in the systemic inflammatory markers mentioned above. At baseline and at the 12 month follow-up 132 people with diabetes and subthreshold depression completed a depression questionnaire (CES-D). A significant improvement of depression was operationalized as a reduction by 9.1 points of the depression score (reliable change index). At both measurement points blood samples for the determination of the systemic inflammatory markers were drawn and analyzed in a central laboratory using the same assays and plates for baseline as well as for follow-up samples. The multivariate analysis was adjusted for age, sex, BMI, HbA1c, diabetes type, macrovascular disease and medication intake (statins, NSAID, anti-coagulant drugs, thyroid medication). Pre-post data were available for 132 people with diabetes (age 44.5 ± 13.7 yrs., 44.1 % female, HbA1c 8.8 ± 1.7%, 64.1% type 1 diabetes, CES-D score 23.4 ± 8.0). At baseline IL-1RA was significantly correlated with the depression score (ß=0.135, p=0.026). Patients with a significant reduction of their depression score at the 12 month follow-up had significant lower IL-1RA (396 ± 51 vs. 540 ± 32 pg/ml; p=0.034) and IL-18 serum levels (270 ± 29 vs. 337 ± 19 pg/ml; p=0.023). In addition, there was a significant interaction effect between IL-1RA reduction and diabetes type (more pronounced reduction in type-2-diabetes).In the cross-sectional as well as in the longitudinal responder analyses, IL-1RA levels showed a significant association with elevated depression scores as well as with the reduction of depression scores. In addition, people with a significant reduction of their depression score had a significant lower IL-18 level at followup. Besides lifestyle factors, adherence and glycemic control, systemic inflammatory processes involving cytokines of the IL-1 family might present a mediating mechanism between depression and the prognosis of diabetes. Supported by ‘Competence Network for Diabetes mellitus’ funded by the BMBF (FKZ 01GI1107)