Background: A significant proportion of patients with ST-segment elevation myocardial infarction (STEMI) have multivessel coronary artery disease (MVD), and they are at high risk for recurrent cardiac events. The aim of the present study was to analyze the impact of MVD on long-term cardiovascular mortality in STEMI patients treated with primary percutaneous coronary intervention (pPCI). Method: This study included 3,115 consecutive STEMI patients hospitalized in the Coronary Care Unit of the Clinical Centre of Serbia, between November 2005 and January 2012. Patients were divided in two groups: MVD and no MVD. MVD disease was defined as stenosis greater than 50% by visual assessment in more than one major coronary artery. Primary PCI was limited to the infarct-related artery (IRA). Cardiovascular mortality was defined as any death from cardiovascular reason (myocardial reinfarction, low-output heart failure, and sudden death). Patients presenting with cardiogenic shock were excluded. Patients were followed-up for 6 years after enrollment. Results: Among 3,115 analyzed patients, 1,352 (43.4%) patients had no MVD and 1,763 (56.6%) had MVD; among patients with MVD, 926 (52.6%) had two-vessel disease and 837 (47.4%) had three-vessel disease. Compared with patients with single-vessel disease, patients with MVD were older, had longer pain duration, and presented more often with heart failure; they were more likely to have previous coronary artery disease, diabetes, hypertension, and chronic kidney disease; post-procedural flow TIMI <3 was more frequently observed in patients with MVD than in patients with no MVD (5.9% vs. 3.1%, p <0.001). Patients with MVD had lower left ventricular ejection fraction than patients with single-vessel disease: 45% (interquartile range [IQR] 40¬–55%) vs. 50% (IQR 43–55%), p <0.001. Revascularization of non-IRA lesions was performed at index hospitalization in 1,075 (61%) patients, and in 602 (34.1%) patients revascularization was performed in the first few months after pPCI (median 1.5 months, IQR 1–2.5 months); coronary artery bypass grafting was performed in 291 (18.4%) patients and PCI (with stent implantation) in 1,368 (81.6%) patients. Six-year cardiovascular mortality was significantly higher in patients with MVD than in patients with single-vessel disease (10.4% vs. 4.6%, p <0.001). In multivariate Cox regression analysis, MVD remained an independent predictor for 6-year cardiovascular mortality (HR 1.55, 95% CI 1.11–2.06, p = 0.041). Conclusion: In STEMI patients treated with pPCI, the presence of MVD remained an independent predictor for higher long-term cardiovascular mortality despite early revascularization of the remaining stenosis in non-IRA.