Bleeding events have been associated with adverse early and late outcomes in virtually all clinical settings. The mechanism behind this observation remains poorly understood. We sought to determine if the reason might be the provocation of an inflammatory response by bleeding events. In a formal substudy of the ACUITY trial, plasma samples of a range of biomarkers were collected at baseline, discharge, 30 days, and 1 year from 192 patients with acute coronary syndromes (ACS) and were analyzed in a central core laboratory. Temporal changes in biomarker levels were assessed in patients who experienced in-hospital hemorrhagic events, recurrent ischemic events, or neither. Sixteen patients were excluded from the study (7 with incomplete samples, 5 undergoing coronary artery bypass grafting (CABG) during index hospitalization; 1 had both bleeding and ischemic events). Median high sensitivity C-reactive protein (hs-CRP) levels (mg/l) increased significantly more from admission to discharge among the 9 patients who experienced an in-hospital major bleed compared to either the 9 patients who had a recurrent ischemic event (+6.0 vs. +0.70, P = 0.04) or the 151 patients who had no event (+6.0 vs. +0.60, P = 0.003). Compared to patients with no in-hospital events, median interleukin-6 (IL-6) levels (pg/ml) increased from admission to hospital discharge non-significantly in those with a bleeding event (+0.92 vs. +2.46, P = 0.55) and in those who experienced an in-hospital recurrent ischemic event (+0.92 vs. +3.60, P = 0.09). These data suggest that major bleeding is associated with development of a pro-inflammatory state. If confirmed, this mechanism may in part explain the poor prognosis of patients experiencing an acute hemorrhagic event.