Inflammatory response and hemodilution are the main drawbacks of extracorporeal circulation. We hypothesize that the use of miniaturized extracorporeal circulation (MECC) might lower the systemic and myocardial inflammatory patterns compared with a standard system (SECC) and off-pump coronary artery bypass grafting (OPCABG). Sixty-one patients undergoing isolated coronary artery bypass graft were prospectively randomized to MECC (n = 19), SECC (n = 20), or OPCABG (n = 22). Blood samples were collected from radial artery and coronary sinus to analyze blood lactate, hemodilution, and markers for inflammation and endothelial activation such as tumor necrosis factor (TNF)-α, interleukin-6, monocyte chemotactic protein-1, and E-selectin. No differences were observed in early clinical outcome. Interleukin -6 levels increased in every group during and after cardiac surgery, whereas TNF-α values grew in the SECC group (p = 0.05). E-selectin systemic values decreased during and after operation (p = 0.001) in every group. Monocyte chemotactic protein-1 systemic and cardiac levels raised only in SECC group (p = 0.014). In conclusion, MECC is comparable to SECC and OPCABG in the clinical outcome of low-risk patients, and it might be extensively used with no additional intraoperative risk. The analysis of the inflammatory patterns of endothelial activation shows MECC as effective as OPCABG, suggesting further studies to clarify MECC recommendation in high-risk patients.