AIMS: (1) To describe changes in arterial stiffness and heart rate variability (HRV) over a 5-year interval, (2) examine changes by sex and race-ethnicity, and (3) evaluate the risk factors associated with the longitudinal changes in arterial stiffness and HRV. METHODS: Participants with youth-onset type 2 diabetes enrolled in the observational follow-up phase of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial had arterial stiffness [(pulse wave velocity, augmentation index, brachial distensibility] and six indices of HRV measured 5 years apart. Multivariable linear regression models assessed risk factors associated with changes in the outcomes over time. RESULTS: At initial vascular assessment, the 304 participants were a mean age of 21 years, 34% male, and had a mean diabetes duration of 8 years. In more than half the cohort pulse wave velocity, augmentation index and HRV increased over 5 years (p<0.01). Brachial distensibility did not change. There were no differences in the 5-year change by race/ethnicity except for a single HRV measure, where non-Hispanic Blacks had greater worsening of parasympathetic function compared to non-Hispanic Whites, p = 0.008. Blood pressure was related to greater worsening in augmentation index and pulse wave velocity. Higher hemoglobin A1c over time was related to worsening pulse wave velocity and HRV. CONCLUSIONS: Arterial stiffness and HRV worsened over 5 years. Blood pressure and glycemic control may be potential targets to influence adverse changes in arterial stiffness and HRV in young adults with youth-onset type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00081328.