Background and Objective: Inflammation plays a role in the early onset of cardiovascular disease. However, longitudinal studies on this topic, especially in South African populations, are scant. We explored whether early changes in vascular structure are associated with changes in inflammation. Methods: We investigated 303 South African teachers aged 20–65 years at two intervals, three years apart. Standardised methods were used to determine carotid intima-media thickness (IMT) and cross-sectional wall area (CSWA) as measures of vascular structure, as well as the inflammatory markers soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein (CRP) and interleukin-6 (IL-6) at baseline and follow-up. Results: IMT and CSWA were higher, while CRP was lower at follow-up than at baseline. After adjusting for confounding factors, percent change in IMT was inversely associated with percent change in suPAR (β = –0.12, p = 0.036; adjusted R2 = 0.16) only, and only in the highest tertile of percent change in suPAR (r = –0.31; p = 0.002). Conclusion: The early structural changes observed are not related to higher inflammatory levels in this South African population. Future studies are needed to investigate the possible protective effect of suPAR on early changes in vascular structure, especially with the focus on cardiovascular disease prevention.