OBJECTIVE Endogenous and exogenous insulin is suggested to stimulate hypertrophic wound-healing responses and therefore may promote neointimal hyperplasia and restenosis after balloon angioplasty. The ratio of C-peptide to insulin reflects endogenous insulin secretion. In diabetic patients with insulin substitution, lower ratios display a higher proportion of exogenous insulin. The association and interaction of insulin and C-peptide with restenosis after percutaneous transluminal angioplasty (PTA) was investigated in type II diabetic and nondiabetic patients. METHODS The study group included 76 patients (median age, 68 years; interquartile range [IQR], 58-74 years; 55 men [72%]; 31 patients [41%] with type II diabetes) with intermittent claudication (n = 49; 64%) or critical limb ischemia (n = 27; 36%) who underwent primary successful femoral PTA. C-peptide and insulin levels were measured at baseline, and patients were followed to determine restenosis (> or =50%) at 12 months by color-coded duplex sonography. RESULTS Restenosis was found in 34 patients (45%) at 12 months. Patients with restenosis had higher insulin levels (median, 21.3 microU/mL IQR, 11.3-35.5 microU/mL) and a lower C-peptide/insulin ratio (median, 16; IQR, 10-21) compared with patients without restenosis (median insulin level, 11.6 microU/mL; IQR, 9.1-22.0 microU/mL [P = .008]; median ratio, 19 [IQR, 17-25], P = .039). In nondiabetic patients, insulin levels were significantly associated with restenosis (P = .046), whereas the ratio of C-peptide to insulin showed no association with restenosis. In patients with type II diabetes (n = 31; 41%), in contrast, the C-peptide/insulin ratio was associated with restenosis (P = .047), whereas insulin levels showed no significant association with restenosis (P = .14). CONCLUSIONS Insulin levels and the C-peptide/insulin ratio were associated with restenosis after femoral PTA. Exogenous and endogenous insulin may play a role in the pathogenesis of recurrent lumen loss after balloon angioplasty.