Background: There is a paucity of data comparing pharmacoinvasive treatment (PI) versus primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) in real world patients. Methods: We employed the Korea Acute Myocardial Infarction Registry to identify patients with STEMI who received either PI defined as fibrinolysis followed by PCI (rescue/urgent or elective) or PPCI. Patients receiving facilitated PCI within 3 hours from fibrinolysis were excluded. Propensity-matched 12-month clinical outcome was compared between the 2 groups. Results: In all patients (n = 9,586), PI group (n = 708) was younger, more often male, smokers, more likely to have typical chest pain and off-hour hospital arrival. PPCI group (n = 8,878) was more likely to have diabetes, lower blood pressure, higher Killip class and to receive glycoprotein IIb/IIIa inhibitors. PI group had shorter symptom-to-first medical contact (FMC) time (60 min vs. 80 min, p < 0.001), symptom-to-reperfusion time (165 min vs. 255 min, p < 0.001), and higher rate of pre-PCI Thrombolysis In Myocardial Infarction (TIMI) 3 (50.6% vs. 13.6%, p < 0.001). However, rate of post-PCI TIMI 3 was similar between the 2 groups. After propensity matching (n = 708 for each group), PI group had similar symptom-to-FMC time but had shorter symptom-to-reperfusion time (165 min vs. 240 min, p < 0.001), higher pre-PCI TIMI 3 rate (15.8% vs. 50.6%, p < 0.001) with similar post-PCI TIMI 3 rate. In all patients, PI group had lower rates of 12-month death (4.4% vs. 6.4%, hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.44 to 0.92, p = 0.015) and major adverse cardiac events (MACE: composite of death, recurrent myocardial infarction, repeat revascularization) (7.5% vs. 9.5%, HR: 0.69, 95% CI: 0.52 to 0.92, p = 0.010). In propensity-matched cohorts, 12-month mortality and MACE were similar between PI and PPCI: 4.4% vs. 2.8%, HR: 1.60, 95% CI: 0.91 to 2.84, p = 0.105 and 7.5% vs. 7.6%, HR: 0.96, 95% CI: 0.65 to 1.41, p = 0.827, respectively. Conclusions: In this large observational study with propensity-matched analysis, STEMI patients receiving PI, compared to PPCI, had shorter symptom-to-reperfusion time, higher culprit-vessel patency, and similar 12-month clinical outcome.