OBJECTIVES: We hypothesized that the prophylactic administration of sodium nitroprusside (NTP) during saphenous vein graft (SVG) PCI would ameliorate the detrimental effects of distal embolization and reduce the frequency and magnitude of post-procedural myonecrosis. METHODS: Sixty-four consecutive patients with normal preprocedural cardiac enzymes underwent SVG PCI without embolic protection devices and received prophylactic intragraft NTP before initial device activation. For each case, 2 control patients were selected in reverse chronologic order and were matched for stent use, thromboatherectomy device use, clinical presentation, presence of thrombus and pre-PCI thrombolysis in myocardial infarction (TIMI) flow. RESULTS: Mean patient age was 66 ± 10 years, 78% of whom were males. Stent and thromboatherectomy use was 95.3% and 3.1%, respectively in both groups (p ≤ ns). Prior to intervention, TIMI < 3 flow was present in 26.6% of cases and in 24.2% of control patients (p ≤ ns). Thrombus was present in 20.3% of cases and in 19.5% of controls (p ≤ ns). Post-PCI creatinine kinase (CK)-MB elevation > 3 x the upper limit of normal (ULN) occurred in 6.3% of cases vs. 16.4% of controls (p ≤ 0.049) and > 5 x ULN in 1.6% of cases vs.10.9% of controls (p ≤ 0.022). In a multivariate regression model that included stent use, in-stent restenosis, thrombus presence, preprocedural TIMI 3 flow, MI as procedural indication, NTP and glycoprotein IIb/IIIa use, NTP was the only independent and significant predictor of reduced post-procedural CK-MB elevation > 5 x ULN. CONCLUSION: Prophylactic administration of intragraft NTP during SVG PCIs results in a lower frequency and magnitude of post-procedural cardiac enzyme elevation.