Coronary plaque rupture mediating acute ST segment elevation myocardial infarction (STEMI) is associated with a systemic inflammatory response. Whether early temporal changes in inflammatory biomarkers are associated with angiographic and electrocardiographic markers of reperfusion and subsequent clinical outcomes is unclear. In the APEX-AMI biomarker substudy, 376 patients with STEMI had inflammatory biomarkers measured at the time of hospital presentation and 24 h later. The primary outcome was the 90-day composite of death, shock, or heart failure. Secondary reperfusion outcomes were (1) worst least residual ST segment elevation (ST-E: <1 mm, 1 to <2 mm, ≥2 mm) and (2) post-percutaneous coronary intervention (PCI) TIMI flow grade (0/1/2 vs 3) and TIMI myocardial perfusion grade (TMPG 0/1 vs 2/3). The 90-day incidence of death, shock or heart failure was 21.3 % in this cohort. Electrocardiographic reperfusion (worst residual ST-E <1 mm, 1 to <2 mm, ≥2 mm) was associated with differences in 24 h change in N-terminal proB-type natriuretic peptide (NT-proBNP) (1192.8, 1332.5, 1859.0 ng/mL; p = 0.043) and the pro-inflammatory cytokines Interleukin (IL)-6 (14.0, 13.6, 22.1 pg/mL; p = 0.016), IL-12 (-0.5, -0.9, -0.1 pg/mL; p = 0.013), and tumor necrosis factor α (TNFα) (1.0, 0.6, 3.6 pg/mL; p = 0.023). Angiographic reperfusion (TMPG 0/1 vs 2/3) was associated with changes in median NT-proBNP (2649.3, 1382.7 ng/mL; p = 0.002) and IL-6 (28.7, 15.1; p = 0.040). After adjustment for baseline covariates, the 24 h change in the pro-inflammatory cytokine TNFα [hazard ratio (HR) 0.49; 95 % CI 0.26-0.95; p = 0.035] and the anti-inflammatory cytokine IL 10 (HR 1.41; 95 % CI 1.06-1.87; p = 0.018) were independently associated with the primary composite outcome. Successful coronary reperfusion was associated with less systemic inflammatory response and greater temporal inflammatory changes were independently associated with higher 90-day composite of death, shock, or heart failure. These findings provide support for an association between success of reperfusion, an acute STEMI inflammatory response and subsequent clinical outcomes.