BACKGROUND: Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration. MATERIALS AND METHODS: Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality. RESULTS: The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (ΔQ5-Q1 = - 2.39 years), a higher BMI (ΔQ5-Q1 = + 0.92 kg/m2), an unfavorable lipid profile, i.e. lower levels of HDL-C (ΔQ5-Q1 = - 0.06 mmol/mol) and higher triglycerides (ΔQ5-Q1 =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent. CONCLUSIONS: Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.