Off-pump coronary artery bypass surgery reduces the myocardial injury associated with on pump surgery with cardiopulmonary bypass (CPB) and ischemic-cardioplegic arrest (CA). We sought to find a mechanistic explanation for this by comparing the transcriptomic changes in the myocardium of patients undergoing on- and off-pump surgery. Transcriptomic analyses were performed on left ventricular biopsies obtained from patients prior to (pre-op) and after completion of all coronary anastomoses (post-op). Microarray results were validated with real-time polymerase chain reaction. In on-pump group, 68 genes were upregulated in post-op vs. pre-op biopsies (P < 0.01, >or=2-fold). They included inflammatory genes CCL3 and CCL4, apoptotic gene GADD45B and prostaglandin synthesis gene PTGS2 (COX-2). In the off-pump group, 17 genes were upregulated in post-op vs. pre-op biopsies (P < 0.01, >or=2-fold), all shared with on-pump patients. To uncover the genes implicated in CPB and ischemic-CA response, we compared the postoperative gene profiles of the two groups. Thirty-eight genes were upregulated in the on-pump vs. off-pump patients (P < 0.01, >or=2-fold). On-pump surgery induces injury-related response, as demonstrated by the upregulation of apoptosis and remodeling markers, whereas off-pump surgery ameliorates that by mainly upregulating a cytoprotective genetic program. Blood levels of the identified cytokines and chemokines followed the same pattern obtained by transcriptomics, suggesting that the myocardium is a likely source for these proteomic changes. In conclusion, off-pump surgery is associated with fewer alterations in gene expression connected with inflammation, apoptosis, and remodeling seen after on-pump surgery with CPB and ischemic-CA.