Background: Levels of high-sensitivity C-reactive protein (hs-CRP) and adiponectin, reflecting chronic inflammation, are associated with cardiovascular disease in type 2 diabetes. The long-term effects of multifactorial therapy in type 2 diabetes patients on CRP and adiponectin are unknown. Methods: The ADDITION-NL study is a randomized clinical trial among screen-detected type 2 diabetes patients, randomized to intensive treatment (HbA1c <7.0% (53 mmol/mol), blood pressure ≤135/85 mmHg, total cholesterol ≤3.5 mmol/L) or routine care. Hs-CRP and adiponectin were measured before and 1, 2 and 6 years after inclusion. We analysed the effectiveness of the intervention on hs-CRP and adiponectin levels using a mixed effects model, taking into account practice, baseline levels and different medications. Results: A total of 424 patients were included (intensive care n=235; routine care n=189). Both groups were well matched. Body mass index, systolic blood pressure, total cholesterol and HbA1c improved significantly more in the intensive care group compared to routine care group. Levels of hs-CRP decreased significantly in both treatment groups over time. Mean hs-CRP in the routine care group was 24% higher (p=0.0027) than in the intensive treatment group during follow-up. After an initial increase the adiponectin values levelled off to nearly baseline values in both groups. The difference between the two groups after 6 years was 0.44 μg/mL (p=0.27). Conclusions: Intensified multifactorial treatment in type 2 diabetes results in an enhanced decrease in hs-CRP. Whether this is clinically meaningful remains uncertain. The link to adiponectin seems to be more complex.