The prognostic significance of inflammatory markers on the long-term risk of major adverse cardiovascular and cerebrovascular events (MACCE) in older NSTEACS patients remains unclear. NSTEACS patients aged 75 and older were recruited to the multicentre cohort study Improve Cardiovascular Outcomes in High-Risk PatieNts with Acute Coronary Syndrome (ICON1). Inflammatory markers including interleukin-6 (IL-6), myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), fibrinogen and tumor necrosis factor-alpha (TNF-α) were collected at baseline. Primary outcome was MACCE consisting of all-cause mortality, reinfarction, stroke/transient ischaemic attack, urgent revascularization, and significant bleeding at 5-year follow-up. There were 230 patients with baseline IL-6 (mean age 80.9 [interquartile range (IQR):78.2-83.9] years). High IL-6 was not associated with MACCE, but high IL-6 was independently associated with all-cause mortality (adjusted hazard ratio [aHR]: 2.26 [95% Confidence Interval (CI):1.34-3.82]; P = 0.002). For patients with hsCRP (n = 260, mean age 80.9 [IQR:77.9-84.1] years), higher levels were significantly associated with increased risk of MACCE (aHR:1.77 [95% CI:1.26-2.49], P = 0.001). In the cohort with MPO (230 patients, mean age 80.9 [IQR:78.2-83.9] years), lower MPO was independently associated with the risk of MACCE (aHR: 0.67 [95%CI:0.46-0.96]; P = 0.029). There was no prognostic significance with fibrinogen and TNF-α. Among older NSTEACS patients, elevated IL-6 and hsCRP were associated with increased risk of all-cause mortality and MACCE, respectively. Low MPO levels were associated with higher MACCE. Further studies are required to determine how these biomarkers should influence treatment strategy in this understudied subset. NCT01933581.