Background Restenosis complicates 30% to 40% of angioplasty procedures and may be unrelated to traditional coronary risk factors. Homocysteine, lipoprotein(a), and methylenetetrahydrofolate reductase (MTHFR 677T) (a genetic determinant of plasma homocysteine concentrations) are novel risk factors for coronary artery disease. Their roles in restenosis are unclear, and the potential synergism between homocysteine and lipoprotein(a) has not previously been studied. The objective of this study was to determine the relations among homocysteine, lipoprotein (a), MTHFR 677T, and restenosis after percutaneous transluminal coronary angioplasty. Methods This prospective study enrolled patients with successful elective percutaneous transluminal coronary angioplasty or stenting of a single, de novo, native coronary lesion. Fasting blood was drawn the morning of the procedure for homocysteine, lipoprotein(a), and MTHFR 677T. Follow-up angiography was performed 6 months after the procedure or earlier if clinically indicated. All cineangiograms were analyzed quantitatively. Results A total of 144 (92%) of 156 eligible patients underwent follow-up coronary angiography. The overall angiographic restenosis rate (residual stenosis >50%) was 31%. Mean homocysteine concentration was 10.1 ± 3.7 μmol/L. Plasma homocysteine concentrations were not significantly different in patients with or without angiographic restenosis (9.6 ± 3.3 vs 10.3 ± 3.8 μmol/L; P =.31). Mean lipoprotein(a) concentration was 21.2 ± 20.1 mg/dL. Plasma lipoprotein(a) concentrations were not significantly different in patients with or without restenosis (21.9 ± 21.8 vs 20.9 ± 19.5 mg/dL). Homozygosity for MTHFR 677T was present in 6.5% and was not associated with increased restenosis. No interaction between homocysteine and lipoprotein(a) was detected. Conclusions Homocysteine, lipoprotein(a), and MTHFR 677T are not associated with restenosis after percutaneous transluminal coronary angioplasty. (Am Heart J 2000;140:272-8.)