Background The relative efficacy and safety of ticagrelor and prasugrel based dual antiplatelet therapy strategies according to the platelet count (PC) in patients with acute coronary syndromes (ACS) have not been defined. Methods This is a posthoc analysis of the ISAR-REACT 5 trial, in which patients presenting with ACS were randomized to treatment with ticagrelor versus prasugrel. Patients were divided into quartiles according to PC. The primary endpoint was incidence of death, myocardial infarction, or stroke, and the safety endpoint was incidence of BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 12 months. Results A total of 3,943 patients with known PC (997 patients in quartile 1 (Q1), 1,003 in quartile 2 (Q2) [205 ± 10.3 × 109/L], 961 patients in quartile 3 (Q3) [241 ± 11.7 × 109/L], and 982 patients in quartile 4 (Q4) [317 ± 68.6 × 109/L]). There was no significant interaction between treatment arm (ticagrelor vs. prasugrel) and PC group with respect to primary endpoint (Q1: 8.8 vs. 6.3%, hazard ratio [HR] =1.41, 95% confidence interval [CI]: 0.89–2.23; p = 0.148; Q2: 9.9 vs. 5.8%, HR = 1.68, 95% CI: 1.06–2.66; p = 0.027; Q3: 7.8 vs. 5.5%, HR = 1.43, 95% CI: 0.87–2.37; p = 0.159; Q4: 10.1 vs. 10.1%, HR = 1.05, 95% CI: 0.71–1.57; p = 0.799; p for interaction [p int] = 0.482) and with respect to bleeding endpoint (Q1: 5.8 vs. 4.2%, HR = 1.41, 95% CI: 0.76–2.63; p = 0.279; Q2: 6.4 vs. 3.7%, HR = 1.62, 95% CI: 0.85–2.06; p = 0.140; Q3: 4.4 vs. 3.0%, HR = 1.53, 95% CI: 0.73–3.18; p = 0.258; Q4: 5.6 vs. 8.5%, HR = 0.67, 95% CI: 0.40–1.14; p = 0.138, p int = 0.102). Conclusions In this analysis, incidences of ischemic and bleeding events at 12 months are comparable across quartiles of platelet count.