Cardiopulmonary bypass (CPB) may trigger organs damage, including kidney injury, due to a massive cytokine release. In this observational, prospective study, we analyzed the possible impact of chronic treatment with ACE-Inhibitors (ACE-I) on the inflammatory response and renal function after CPB. Sixty-nine patients undergoing major cardiac surgery with CPB were enrolled. Patients were stratified according to long-term (> 6 mo.) ACE-I use (n = 38) or not (n = 31). The primary endpoint was the change in IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF alpha, EGF and VEGF plasma levels. Secondary (renal) endpoints were postoperative acute kidney injury (AKI), recovery of baseline GFR values and the absolute changes in renal function indexes. After CPB, IL-1alpha, IL-1beta, IL-4 and TNF-alpha remained stable over time while a significant decrease in IL-2 levels was noticed in the ACE-I group (p = 0.01). IL-6 and IL-8 increased after surgery and tended to decrease after 48 h. IL-10 levels showed a similar variation, but both their rise and decrease were more pronounced in patients under ACE-I treatment (p = 0.007). Finally, VEGF and EGF showed a marked initial decrease with a tendency to normalization 10 days after surgery (p for trend ranging from 0.01 to 0.001). The occurrence of AKI within 2 days after surgery, the rate of GFR recovery and the absolute changes in renal function indexes were not statistically different between groups. Chronic, long-term ACE-I treatment may influence the inflammatory response following CPB. On the other hand, this drug class apparently has neutral impact on perioperative renal outcomes.