Background Patients who experience in-hospital ST-segment elevation myocardial infarction (iSTEMI) represent a uniquely high-risk cohort owing to delays in diagnosis, prolonged time to reperfusion and increased mortality. Quality initiatives aimed at improving the care of this vulnerable, yet understudied population are needed.Methods This study included consecutive patients with iSTEMI treated with percutaneous coronary intervention (PCI) between 1 January 2011 and 15 July 2019 at a single, tertiary referral centre. A comprehensive iSTEMI protocol (CSP) was implemented on 15 July 2014, incorporating: (1) cardiology fellow activation of the catheterisation lab using standardised criteria, (2) nursing chest pain protocol, (3) improved electronic access to electrocardiographic studies, (4) checklist for initial triage and management, (5) 24/7/365 catheterisation lab readiness and (6) radial-first PCI approach. Key metrics and clinical outcomes were compared before and after CSP implementation.Results Among 125 total subjects, the post-CSP cohort (n=81) was younger, had more males and were more likely to be hospitalised for cardiac-related reasons relative to the pre-CSP cohort (n=44) who were more likely hospitalised for operative-related aetiologies. After CSP adoption, median ECG-to-first-device-activation time decreased from 113 min to 64 min (p