The objective of this study was to evaluate the clinical and angiographic factors associated with significant saphenous vein graft (SVG) atherosclerosis progression at mid-term follow-up in a series of unselected coronary patients who had previously received a coronary artery bypass graft (CABG). A total of 123 SVGs from 86 patients who underwent cardiac catheterization twice, 15 +/- 12 months apart, were included in the study. None of the SVGs presented any > or =50% diameter stenosis (DS) lesion or underwent any intervention at baseline. All SVGs were divided into 3 segments and each SVG segment was scored from 0 to 3 depending on the presence of lesions, with percent DS ranging from 0% to 19% (score 0), 20% to 29% (score 1), 30% to 39% (score 2), and > or =40% (score 3). The SVG atherosclerotic burden score (ABS) was calculated by adding the score obtained for each of the 3 SVG segments. Significant progression was defined as > or =10% increase in lesion percent DS or > or =0.6 mm decrease in minimal lumen diameter between baseline and follow-up studies. Mean age of the study population was 66 +/- 9 years, and most of the patients were receiving statin therapy with mean low-density lipoprotein cholesterol of 85 +/- 26 mg/dl. Significant angiographic progression occurred in > or =1 SVG in 41 patients (48%). On multivariate analysis, the variables associated with SVG atherosclerosis progression were SVG ABS (odds ratio [OR], 1.52 for each increase of 1 point in SVG ABS; 95% confidence interval [CI] 1.1 to 2.29) and high-density lipoprotein (HDL) cholesterol (OR 1.38 for each decrease of 5 mg/dl in HDL cholesterol levels, 95% CI 1.09 to 1.85). Twenty-two patients (26%) had a cardiac event at follow-up related to SVG disease progression. The percent DS of the SVG segment at baseline was associated with SVG disease progression leading to a cardiac event (OR 3.67 for each increase of 5% in percent DS, 95% CI 2.11 to 6.38). In conclusion, simple clinical and angiographic variables such as HDL cholesterol, ABS, and lesion severity remain independent predictors of significant SVG atherosclerosis progression in mild to moderately diseased SVGs despite mean low-density lipoprotein levels <90 mg/dl.