Background Cardiovascular disease depends on the duration and time course of risk factor exposure. Previous reports on risk factors of progression of carotid intima‐media thickness (cIMT) in the young were mostly restricted to high‐risk populations or susceptible to certain types of bias. We aimed to unravel a risk factor signature for early vessel pathology based on repeated ultrasound assessments of the carotid arteries in the general population. Methods and Results Risk factors were assessed in 956 adolescents sampled from the general population with a mean age of 15.8±0.9 years, 56.2% of whom were female. cIMT was measured at baseline and on average 22.5±3.4 months later by high‐resolution ultrasound. Effects of baseline risk factors on cIMT progression were investigated using linear mixed models with multivariable adjustment for potential confounders, which yielded significant associations (given as increase in cIMT for a 1‐SD higher baseline level) for alanine transaminase (5.5 μm; 95% CI: 1.5–9.5), systolic blood pressure (4.7 μm; 0.3–9.2), arterial hypertension (9.5 μm, 0.2–18.7), and non‐high‐density (4.5 μm; 0.7–8.4) and low‐density lipoprotein cholesterol (4.3 μm; 0.5–8.1). Conclusions Systolic blood pressure, arterial hypertension, low‐density and non‐high‐density lipoprotein cholesterol, and alanine transaminase predicted cIMT progression in adolescents, even though risk factor levels were predominantly within established reference ranges. These findings reemphasize the necessity to initiate prevention early in life and challenge the current focus of guideline recommendations on high‐risk youngsters. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03929692.