Myointimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) is a key component of the process of restenosis. The c‐myc is a critical cell‐cycle division protein involved in the formation of neointima. We evaluated the long‐term impact of local delivery of c‐myc neutrally charged antisense oligonucleotides (Resten‐NG) on myointimal hyperplasia after PTCA in a rabbit model. PTCA was performed in the iliac arteries of 25 New Zealand white rabbits, using a Transport\T catheter at 8 atm for 30 sec, three times; 500 μg Resten‐NG (n = 11) or saline (n = 14) was delivered to the PTCA site at 2 atm with the outer balloon for 2 min. The diet was supplemented with 0.25% cholesterol for 10 days before and 60 days after PTCA. Angiography was performed at harvest, and vessels were fixed in formalin, processed, and stained with hematoxylin and eosin (H&E) and Movat. Quantitative angiography showed that local delivery of antisense c‐myc at PTCA reduced late luminal loss from 1.8 ± 0.30 mm in control animals to 0.90 ± 0.30 mm in the treatment group (P = 0.001). Histological analysis by planimetry showed that intimal areas were 1.67 ± 0.44 mm2 and 0.82 ± 0.32 mm2 in the control and antisense delivery groups, respectively (P < 0.05). We conclude that local delivery of Resten‐NG inhibited myointimal hyperplasia after PTCA in cholesterol‐fed rabbits for up to 60 days. Cathet Cardiovasc Intervent 2001;54:247–256. © 2001 Wiley‐Liss, Inc.