Objective: To examine the optimal duration of antibiotic prophylaxis in major cardiovascular surgery. Methods: In the past 15 years, four prospective randomized, controlled studies, conducted by the same group of authors, compared seven prophylactic antimicrobial regimens in 2970 patients undergoing major cardiovascular surgery. In 1980/81, a 4-day cefazolin (CFZ) prophylaxis was compared with a 2-day cefuroxime (CFX) administration (n=566). In 1982/83, a 2-day CFX prophylaxis was compared with a two shot ceftriaxone (CRO) prophylaxis (n=512). In 1984/87, a 1-day CFZ prophylaxis was compared with a single shot prophylaxis of CRO (n=883). In 1994/1995, a 4 day combination of amoxicillin (AM) and netilmicin (NET) prophylaxis was compared with a single shot prophylaxis of CFX (n=1009). Results: Total infection rate varied between 4.5 and 5.7%, despite different antimicrobial regimen used and their varying duration. Wound infection rate was 1.1% (range 0.4-2.5%), sepsis rate was 0.8% (range 0.4-1.6%), pneumonia rate 2% (0.7-2.9%), urinary tract infection rate 0.4% (range 0-1.4%), and central venous catheter-related infection rate was 0.4% (0-1%). The 30-day mortality rate was 1.3% (range 0.4-2%). All these differences were not statistically significant. Conclusions: A low infection rate (range 4.5-5.7%) occurred despite changes in duration of various prophylactic antibiotic regimen with cephalosporins of first, second or third generation. As a single shot prophylaxis could nowadays successfully be used in cardiovascular surgery, no postoperative antibiotics should be used, unless an intraoperative or a postoperative infection is documented or in presence of major perioperative complication