The most serious infection after coronary artery bypass grafting (CABG) is mediastinitis following deep sternal wound infection. Antibiotic prophylaxis for at least 48 hours has been recommended. In this trial 551 consecutive patients were randomized to receive ceftriaxone in a single dose or cefuroxime thrice daily until the end of the second postoperative day. The overall infection rate was 7.7% in the ceftriaxone and 8.3% in the cefuroxime group, and the incidence of deep sternal infection was 2.9% in both groups. Significant risk factors for such infection were chronic respiratory disease (p < 0.001) and diabetes (p < 0.01). The antibiotic prophylaxis had no harmful effects on the colonic flora in either group. Acquisition and delivery costs for the prophylactic agents were three times higher in the cefuroxime than in the ceftriaxone group. Both antibiotics are concluded to be equally safe and effective. Single-dose ceftriaxone prophylaxis is as effective as cefuroxime given for 48 hours postoperatively. Single-dose ceftriaxone is also simple to use.