Current guidelines recommend initiation of a P2Y(12) inhibitor for all patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) at the time of diagnosis (pre-treatment); however, there are no randomized trials directly comparing pre-treatment with initiation at the time of angiography to support this practice. We explore clinical and institutional parameters potentially associated with benefit with this strategy in a decision-analytic model based on available evidence from randomised trials. A decision analysis model was constructed comparing three P2Y(12) inhibitors in addition to aspirin in patients with NSTE-ACS. Based on clinical trial data, the cumulative probability of 30 day mortality, myocardial infarction (MI) and major bleeding were determined, and used to calculate the net clinical benefit (NCB) with and without pre-treatment. Sensitivity analysis was performed to assess the relationship between NCB and baseline ischemic risk, bleeding risk, time to angiography and local surgical revascularization rates. Pre-treatment with ticagrelor and clopidogrel was associated with a greater than 50% likelihood of providing a >1% increase in 30 day NCB when baseline estimated ischemic risk exceeds 11% and 14%, respectively. Prasugrel pre-treatment did not achieve a greater than 50% probability of an increase in NCB regardless of baseline ischemic risk. Institutional surgical revascularization rates and time to coronary angiography did not correlate with the likelihood of benefit from P2Y(12) pre-treatment. In conclusion, pre-treatment with P2Y(12) inhibition is unlikely to be beneficial to the majority of patients presenting with NSTE-ACS. A tailored assessment of each patient’s individual ischemic and bleeding risk may identify those likely to benefit.