Sodium nitroprusside (SNP), a nitrosovasodilator, increases platelet cyclic GMP levels and inhibits platelet activity in vitro. The antiplatelet properties of SNP are not well established in vivo, however, and consequently are not appreciated by clinicians. In our established model of mechanically stenosed canine coronary arteries (MSCA) with intimal damage, periodic acute platelet thrombus formation (APTF) occurs, followed by embolization distally, which then causes cyclic flow reductions (CFRs) in coronary blood flow. Aspirin (ASA) abolished platelet-mediated CFRs in our model, but they recur when epinephrine (EPI) is infused (0.2 μg/kg/min). SNP was given continuously intravenously (i.v.) to 17 dogs with MSCA; CFRs were abolished in all dogs by SNP at 4.4 ± 2.7 μg/kg/min (mean ± SD). Mean arterial blood pressure (MAP) decreased by 19 ± 9 mm Hg (p < 0.001) from control, while heart rate (HR) increased 35 ± 20 beats/min (p < 0.001). Platelet cyclic GMP levels were 2.9 ± 1.1 pmol/108 platelets before SNP infusion, and increased to 4.3 ± 1.6 pmol/108 platelets (p < 0.05) when CFRs were abolished. CFRs were not renewed during the continued SNP infusion when EPI was infused at 0.2 μg/ kg/min for 20 min in 11 dogs, but CFRs returned within 5–25 min after the SNP infusion was terminated. The return of CFRs occurred together with a decrease in platelet cyclic GMP levels to 3.3 ± 1.4 pmol/108 platelets. These data demonstrate that (a) SNP, an endothelium-derived relaxing factor (EDRF) congener, inhibits platelet-mediated CFRs in vivo; (b) inhibition of platelet function in vivo by SNP occurs in association with increases in platelet cyclic GMP levels; (c) the antiplatelet properties of SNP are rapidly reversible on discontinuation of drug infusion; and (d) these antiplatelet effects of SNP, unlike ASA, are resistant to increases in plasma EPI. This latter observation suggests that by increasing platelet cyclic GMP levels, SNP, and, by analogy EDRF, may block platelet activating pathways in vivo that are not inhibited by ASA. These antiplatelet effects of SNP may contribute to its clinical efficacy in certain vascular disorders.