Background <p>The prospective association of the triglyceride-glucose (TyG) index on carotid atherosclerosis (CA), particularly carotid intima-media thickness (CIMT), remains incompletely defined.</p> Methods <p>A total of 6007 middle-aged and elderly participants were enrolled. Multivariable logistic regression models were used to assess the relationships between the TyG index and changes in CIMT by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs). Stratified analyses according to age, gender, BMI, and baseline CIMT status were performed. The potential modifying effect of gender on the association between TyG and CIMT was evaluated.</p> Results <p>Over 6 years of follow-up, only 1661 (27.65%) participants remained normal CIMT comparing to 3648 (60.73%) at baseline. Among participants with the highest TyG quartile (Q4), 1110 (73.85%) and 709 (47.17%) were detected with progression of CA and newly diagnosed plaques, respectively. After adjustment of confounding factors, participants with higher TyG quartiles are more likely to develop CA with ORs (95% CIs) _{Q2 vs. Q1}1.14 (0.87, 1.49), OR (95% CIs)_{Q3 vs. Q1} 1.25 (0.95, 1.65), and OR (95% CIs)_{Q4 vs. Q1}1.44 (1.06, 1.94), P_trend = 0.016. Significant associations between the TyG index and increased CIMT were primarily observed among middle-aged, male, and overweight individuals. Furthermore, gender was identified as an effect modifier, strengthening the association between TyG and CA progression, particularly among men with pre-existing CIMT thickening.</p> Conclusions <p>A positive association exists between the TyG index and CA progression. Higher baseline TyG quartiles were associated with significant CA progression, and the highest quartile was closely linked to an increased prevalence of carotid plaque.</p> Trial registration <p>ClinicalTrials.gov Identifier NCT01506869.</p>