Methylglyoxal (MG) has been implicated in the development of micro- and macrovascular diabetic complications, but it remains unclear how current treatments of type 2 diabetes affect its circulating levels. In the Danish arm of the ADDITION trial, we (a) described serum MG levels at baseline and at 6-year follow-up among individuals with screen-detected type 2 diabetes, (b) examined the effect of intensive multifactorial treatment compared with routine care on MG, (c) examined the associations between MG and risk factors at baseline and at follow-up and (d) examined the associations between changes in MG and changes in risk factors. Patients in both treatment arms experienced a significant decline in MG from baseline to follow-up, with no effect of allocation to intensive treatment. In cohort analyses, MG was associated with smoking and fasting glucose at baseline and smoking and LDL cholesterol at follow-up. Compared with patients receiving no lipid-lowering treatment, patients receiving lipid-lowering treatment had higher MG at follow-up, and those initiating lipid-lowering treatment experienced a less pronounced decline in MG. Further studies are required to explore any possible effects of the observed decrease in MG in type 2 diabetes patients as well as the potential interplay between MG, lipids, lipid-lowering treatment and smoking.