Background: Optimal adjunctive therapy in ST-segment elevation myocardial infarction (STEMI) patients treated with primary PCI (PPCI) remains a matter of debate. Our aim was to compare the efficacy and safety of bivalirudin to unfractionated heparin (UFH), with or without glycoprotein IIb/IIIa inhibitors (GPI) in a large real-world population, using data from the Swedish national registry, SWEDEHEART. Method: From 2008 to 2014 we identified 23,800 STEMI patients presenting within 12 hours from symptom onset treated with PPCI and UFH ± GPI or bivalirudin±GPI. Primary outcomes included 30-day all-cause mortality and major in-hospital bleeding. Multivariable regression models and propensity score modelling were utilized to study adjusted association between treatment and outcome. Results: Treatment with UFH ± GPI was associated with similar risk of 30-day mortality compared to bivalirudin±GPI (5.3% vs 5.5%, adjusted HR 0.94; 95% CI 0.82–1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between UFH ± GPI and bivalirudin±GPI. In contrast, treatment with UFH ± GPI was associated with a significant higher risk of major in-hospital bleeding (adjusted OR 1.62; 95% CI 1.30–2.03). When including GPI use in the multivariable analysis, the difference was attenuated and no longer significant (adjusted OR 1.25; 95% CI 0.92–1.70). Conclusion: Bivalirudin±GPI was associated with significantly lower risk for major inhospital bleeding but no significant difference in 30-day or one year mortality, stent thrombosis or re-infarction compared with UFH ± GPI. The bleeding reduction associated with bivalirudin could be explained by the greater GPI use with UFH.