Background: ST-segment elevation myocardial infarction (STEMI) mandates rapid percutaneous coronary intervention (PCI) for optimal outcomes. The mortality benefit of primary PCI depends on prompt time to treatment and especially the door-to-balloon time (DTB). Numerous strategies can be used to reduce DTB and thus improve clinical outcomes with primary PCI. The aim of this study was to evaluate the effect of the implementation of critical pathway and audit program for managing acute STEMI to reduce DTB in primary PCI. Methods: Critical pathway protocol for acute STEMI was implemented in January 2008 at our institution and included direct notification to operator from pre-hospital Information Center paramedic or physician at emergency department; pre-hospital activation of catheterization laboratory (Cath Lab) personnel; starting to transport patient to Cath Lab even before all PCI personnel arrive; direct or immediate admission to Cath Lab and obtaining consent during preparing patient at the Cath Lab (initiating anticoagulants and antiplatelets and shaving groin); and performance feedback within 24 to 48 hours. Results: The pre-implementation group (January through December 2007) comprised 32 patients with a median DTB of 506.5 (interquartile range, 27, 1416) minutes, and 15.6% had a DTB <90 minutes. The post-implementation group (January 2008 through June 2010) comprised 220 patients with a median DTB of 70 (interquartile range, 9, 403) minutes, and 72% had a DTB <90 minutes. Post-implementation DTB was significantly shorter than pre-implementation DTB (P<0.0001). In multiple logistic regression model, the critical pathway and audit protocol was the only independent predictor for DTB <90 minutes (HR 71.9, 95% CI 7.8-663.2, p = 0.000). In the 3-year follow-up after critical pathway protocol implementation, the median DTB performance remained stable and improved annually over time (84 min, 58 min, and 52 min, respectively, p = 0.001). Conclusions: Our critical pathway and audit protocol for acute STEMI implemented strategies to reduce DTB for patients with STEMI. DTB was significantly reduced, and the results were sustained over the 3-year follow-up period. Our experience demonstrates the effectiveness and durability of process changes targeting timeliness of primary PCI.