Low levels of Soluble TNF-related apoptosis induced ligand (sTRAIL) seem to be related to worse prognosis after an acute coronary syndrome. PostConditioning (PostCond) may protect the heart from reperfusion injury. We sought to evaluate the impact of PostCond on sTRAIL in relationship to infarct size (area under the curve of Troponin T, AUCTnT) and left ventricle ejection fraction (LVEF) in a series of patients undergoing primary coronary intervention for ST-segment elevation myocardial infarction (STEMI). In a substudy of a randomized trial that tested the effects of PostCond in STEMI-patients, sTRAIL was measured 24 h after reperfusion (PostCond n = 39, Control n = 39). Correlations between sTRAIL and both AUCTnT and LVEF were studied for each study arm. At 24 h, sTRAIL was higher for PostCond vs Controls (46.4 ± 30.6 vs 32.9 ± 23.4, p = 0.031), was negatively related to AUCTnT [B = −0.09, 95 % CI (−0.15 to −0.30), p = 0.005] and was positively related to both in-hospital [B = 0.10, 95 % CI (0.02–0.17), p = 0.018], and follow-up LVEF [B = 0.21, 95 % (0.10–0.32), p = 0.001]. No significant relationship was found for Controls. On multivariate analysis, PostCond was an independent predictor for sTRAIL [B = 12.13 95 % CI (0.40–23.87), p = 0.043]. In conclusion, PostCond positively influenced sTRAIL, which was related to reduced infarct size and better LVEF. Further studies are needed to understand potential mechanisms elicited by PostCond in infarct size reduction.