Anastomotic leakage and septic complications are the most important determinants of postoperative outcome after major surgical resections. Malignant diseases and surgical trauma can influence immune responses and the ability to react against infectious factors, such as bacteria and viruses. Comparable immune suppression can cause viral reactivation in transplantation and trauma patients. In this prospective study, patients who underwent major surgical resections for oesophageal or pancreatic cancer were investigated for the potential involvement of viral reactivation in the development of septic complications. 86 patients (40 oesophageal resections, 27 pancreatic resections, 19 surgical explorations) were included. Viral antigens, viral DNA, antibodies against viral structures (IgG, IgM, IgA) and, in part, viral cultivation were performed for CMV, EBV, HSV1, HSV2, HZV6 and VZV in serum, urine, sputum and swabs from buccal mucosa preoperatively and at postoperative days 1, 3 and 5. Test results were compared with the postoperative outcome (30-day morbidity, in-hospital mortality) and clinical scores (SOFA, TISS). For statistical analyses Student's t-tests and Chi2-tests were used. The overall complication rate was 19.8% (30-day morbidity) with an in-hospital mortality of 1.2% (1/86 patients). Postoperatively, anti-CMV-IgG titres were significantly reduced (p<0.05) and remained suppressed in patients with septic complications. Anti-CMV-gB-IgG were also reduced, but showed considerable interindividual differences. Anti-CMV-IgA and -IgM did not show significant alterations in the postoperative course. In addition, direct viral detection methods did not support viral reactivation in patients in any of the investigated groups. The reduction of anti-CMV antibodies is likely caused by an immune suppression, specifically by reduced B-cell counts after major surgical interventions. Viral reactivation, however, did not occur in the early postoperative period as a specific risk for septic complications.