Background: Nitric oxide (NO) donors, in addition to their vasodilator effect, decrease platelet aggregation and inhibit vascular smooth muscle cell proliferation. These actions could have beneficial effects on restenosis after coronary balloon angioplasty. Methods and Results: In a prospective multicenter, randomized trial, 700 stable coronary patients scheduled for angioplasty received direct NO donors (infusion of linsidomine followed by oral molsidomine) or oral diltiazem. Treatment was started before angioplasty and continued until 12 to 24 hours before follow-up angiography at 6 months. The primary study end point was minimal lumen diameter, assessed by quantitative coronary angiography, 6 months after balloon angioplasty. Clinical variables were well matched in both groups. However, despite intracoronary administration of isosorbide dinitrate, the reference diameter in the NO donor group was significantly greater than in the diltiazem group on the preangioplasty, postangioplasty, and follow-up angiograms. Pretreatment with an NO donor was associated with a modest improvement in the immediate angiographic result compared with pretreatment with diltiazem minimum luminal diameter, 1.94 versus 1.81 mm; P=.001); this improvement was maintained at the 6-month angiographic follow-up (minimal lumen diameter, 1.54 versus 1.38 mm; P=.007). The extent of late luminal narrowing did not differ significantly between groups (loss index in the NO donor and diltiazem groups, 0.35±0.78 and 0.46±0.74, respectively; P=.103). Restenosis, defined as a binary variable (≤50% stenosis), occurred less often in the NO donor group (38.0% versus 46.5%; P=.026). Combined major clinical events (death, nonfatal myocardial infarction, and coronary revascularization) were similar in the two groups (32.2% versus 32.4%). Conclusions: Treatment with linsidomine and molsidomine was associated with a modest improvement in the long-term angiographic result after angioplasty but had no effect on clinical outcome. The improved angiographic result related predominantly to a better immediate procedural result, because late luminal loss did not differ significantly between groups.