BACKGROUND: Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events. OBJECTIVES: This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals. METHODS: Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 ± 4.1 years, 50.3% women). CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol ≥40 mg/dl. A subgroup with optimal CVRFs (n = 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasound-detected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used. RESULTS: Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [×10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels. CONCLUSIONS: Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318).