Background Among patients with STEMI in the ATLANTIC study, pre-hospital administration of ticagrelor improved post-PCI ST-segment resolution and 30-day stent thrombosis. We investigated whether this clinical benefit with pre-hospital ticagrelor differs by ischemic duration. Methods In a post hoc analysis we compared absence of ST-segment resolution post-PCI and stent thrombosis at 30 days between randomized treatment groups (pre-versus in-hospital ticagrelor) stratified by symptom onset to first medical contact (FMC) duration [amp;lt;= 1 hour (n = 773), amp;gt;1 to amp;lt;= 3 hours (n = 772), and amp;gt;3 hours (n = 311)], examining the interaction between randomized treatment strategy and duration of symptom onset to FMC for each outcome. Results Patients presenting later after symptom onset were older, more likely to be female, and have higher baseline risk. Patients with symptom onset to FMC amp;gt;3 hours had the greatest improvement in post-PCI ST-segment elevation resolution with pre-versus in-hospital ticagrelor (absolute risk difference: amp;lt;= 1 hour, 2.9% vs. amp;gt;1 to amp;lt;= 3 hours, 3.6% vs. amp;gt;3 hours, 12.2%; adjusted p for interaction = 0.13), while patients with shorter duration of ischemia had greater improvement in stent thrombosis at 30 days with pre-versus in-hospital ticagrelor (absolute risk difference: amp;lt;= 1 hour, 1.3% vs. amp;gt;1 hour to amp;lt;= 3hours, 0.7% vs. amp;gt;3 hours, 0.4%; adjusted p for interaction = 0.55). Symptom onset to active ticagrelor administration was independently associated with stent thrombosis at 30 days (adjusted OR 1.89 per 100 minute delay, 95% CI 1.20-2.97, P amp;lt; .01), but not post-PCI ST-segment resolution (P = .41). Conclusions The effect of pre-hospital ticagrelor to reduce stent thrombosis was most evident when given early within 3 hours after symptom onset, with delay in ticagrelor administration after symptom onset associated with higher rate of stent thrombosis. These findings re-emphasize the need for early ticagrelor administration in primary PCI treated STEMI patients.